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The clinical response to immune checkpoint inhibitors may vary by tumor type and many tumors present with either primary or acquired resistance to immunotherapy. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for developing biomarkers and for guiding the optimum approach to selecting treatment regimens and sequencing. This is increasingly important for tumors with primary resistance as effective biomarkers in this setting can guide clinicians about appropriate treatment regimen selection in the first-line setting. Multiple potential biological mechanisms of primary resistance have been proposed but most are yet to be validated in prospective clinical cohorts. Individual biomarkers have poor specificity and sensitivity, and the development of validated and integrated predictive models may guide which patient will benefit from monotherapy versus combination therapy. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors (ICIs) are a cornerstone therapy for advanced renal cell carcinoma (RCC). However, significant rates of primary resistance hinder their efficacy, and the underlying mechanisms remain poorly understood. This study aims to unravel the tumor-immune interactions and signaling pathways driving primary resistance to ICIs in RCC. Methods We integrated single-cell RNA sequencing, spatial transcriptomics, and clinical sample analysis to investigate the tumor microenvironment and intercellular signaling. Advanced computational methods, including cell–cell communication networks, pseudotime trajectories, and gene set enrichment analysis (GSEA), were employed to uncover the underlying resistance mechanisms. Results Compared to the sensitive group, the primary resistance group exhibited a significant increase in SPP1-CD44 signaling-mediated interactions between tumor cells and immune cells. These interactions disrupted antigen presentation in immune effector cells and suppressed key chemokine and cytokine pathways, thereby impairing effective immune responses. In contrast, the sensitive group showed more active antigen presentation and cytokine signaling, which facilitated stronger immune responses. Furthermore, the interaction between SPP1-secreting tumor cells and CD44-expressing exhausted CD8 + T cells activated the MAPK signaling pathway within CD8 + Tex cells, exacerbating T cell exhaustion and driving the development of ICI resistance in RCC. Conclusion Our findings reveal a potential mechanism by which SPP1-CD44 signaling mediates tumor-immune cell interactions leading to ICI resistance, providing a theoretical basis for targeting and disrupting this signaling to overcome primary resistance in RCC.

Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Chemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched. Methods: In this study, we performed transcriptome screening of peripheral blood plasma obtained from 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance. Results: Our analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed PRICKLE3, TNFSFI0, ACSLl and EP300 as potential contributors to primary resistance, with SNWl, SENP2 and SMNDCl emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC. Discussion: These findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies. [ABSTRACT FROM AUTHOR]

Advanced biliary tract cancers (BTCs) have gained notoriety among gastrointestinal tumours for their comparatively high incidence of actionable alterations and their compelling benefit from targeted therapies matched to these alterations. Such successes are exemplified by BTC-specific approvals of fibroblast growth factor receptor (FGFR) inhibitors for tumours with FGFR2 rearrangements, as well as mutant isocitrate dehydrogenase 1 inhibitors. Nevertheless, there is a clear absence of therapeutic benefit in a subset of patients despite their tumours fulfilling the current molecular criteria for treatment with these drugs. This results in inefficient management of patients with otherwise bleak prognosis, as well as considerable financial burden. Even among responders, the duration of response is limited, a clinical observation that could be considered unusual as these inhibitors typically target driver genes hypothesised to be responsible for tumour formation. However, BTCs exhibit oncogenic addiction to signalling networks rather than individual genes, and by extension, therapeutic response is dependent on these signalling networks rather than simply the status of the specific target gene. Primary resistance is mediated by co-occurring genetic (DNA) and non-genetic (transcriptional, translational, post-translational) alterations in members of signalling networks that are upstream, downstream, or in parallel pathways to the target alteration. Refining the molecular criteria to select patients is a necessary next step, by incorporating co-occurrence of resistance biomarkers as individual parameters or into predictors of treatment benefit. Characterising the molecular bases of resistance to targeted therapies will fuel next-generation combination treatments, maximising the catchment of responders and enhancing the duration of response.

IntroductionChemoresistance constitutes a prevalent factor that significantly impacts thesurvival of patients undergoing treatment for smal-cell lung cancer (SCLC). Chemotherapy resistance in SCLC patients is generally classified as primary or acquired resistance, each governedby distinct mechanisms that remain inadequately researched.MethodsIn this study, we performed transcriptome screening of peripheral blood plasma obtainedfrom 17 patients before and after receiving combined etoposide and platinum treatment. We firs testimated pseudo-single-cell analysis using xCell and ESTIMATE and identified differentially expressed genes (DEGs), then performed network analysis to discover key hub genes involved in chemotherapy resistance.ResultsOur analysis showed a significant increase in class-switched memory B cell scores acrossboth chemotherapy resistance patterns, indicating their potential crucial role in mediatingresistance. Moreover, network analysis identifed PRICKLE3, TNFSFI0, ACSLl and EP300 as potential contributors to primary resistance, with SNWl, SENP2 and SMNDCl emerging assignificant factors in acquired resistance, providing valuable insights into chemotherapy resistancein SCLC.DiscussionThese findings offer valuable insights for understanding chemotherapy resistance and related gene signatures in SCLC, which could help further biological validation studies.

The discovery of the efficacy of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients has revolutionized lung cancer therapy. Although almost all responders acquire drug resistance within a few years, many studies have revealed several acquired-resistant mechanisms and developed therapeutic strategies countervailing them, most notably against the EGFR T790M gatekeeper mutation. However, little progress has been made in terms of elucidating the mechanisms of primary resistance. Primary resistance may be defined into two types of resistance, clinically representing patients that do not respond (non-responders) to EGFR-TKIs. The first group consists of approximately 10% of patients that are insensitive to EGFR-TKIs from the outset (intrinsic primary resistance), and 20–30% of the second group consists of patients that seem to clinically benefit at first, but experience early relapse within six months (late primary resistance). In this review, we first provide an overview of drug-induced lung cancer dynamics. We then delve into the mechanisms of primary resistance, with a primary focus on two specific subtypes of resistance. We suggest that “intrinsic primary resistance” is characterized by pre-existing somatic and genomic changes and cell of origins, while “late primary resistance” is correlated with the drug-tolerant persister state. Developing therapeutic strategies to overcome primary resistance is crucial to prolonging the duration of EGFR-TKI therapy. Ultimately, this will allow for an enhanced understanding of lung cancer’s evolutional process, leading to the reversal of acquired resistance and the complete eradication of lung cancer.

Li Wang,1,* Fei Quan,2,* Zhen Guo,3 Zhongyu Lu,2 Duoxia Yang,2 Meiqi Shi1 1Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The Medical Department, Nanjing Simcere Medical Laboratory Science Co., Ltd, Nanjing, People’s Republic of China; 3Radiology Department, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meiqi Shi, Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, No. 42, Baiziting, Xuanwu District, Nanjing, Jiangsu, 210009, People’s Republic of China, Tel/Fax +86 25 83283568, Email shimeiqi1963@163.comAbstract: Approximately 10– 20% of patients demonstrate primary resistance to EGFR-TKIs, and different EGFR mutations vary in sensitivity to EGFR-TKIs. We report a case of a 78-year-old male with lung adenocarcinoma that EGFR L858R (AF = 1.32%) coexisting with EGFR S645C (AF = 7.13%) in his diagnosed tissues analyzed by NGS. The patient was primarily resistant to first-line osimertinib and rapidly progressed after pembrolizumab in combination with pemetrexed and bevacizumab, as demonstrated by persistently elevated CEA levels during treatment. ctDNA-based NGS analysis revealed loss of EGFR L858R while persistence of highly abundant EGFR S645C in the pleural fluid and plasma after treatment, suggesting that EGFR L858R may be a subclone. We provide the first clinical evidence of the primary resistance of EGFR S645C to osimertinib and emphasize the importance of identifying clones and subclones. Our patient did not respond to immunotherapy either, and preclinical studies have shown that EGFR S645C activates the MEK signaling pathway, the combination of EGFR-TKIs and MEK inhibitors may be effective.Keywords: EGFR S645C, osimertinib, primary resistance, NSCLC, subclone

Gastrointestinal stromal tumors (GIST) are most common mesenchymal tumors in gastrointestinal tract which originate from interstitial cells of Cajal and characterized by the mutations in the KIT or PDGFRA tyrosine kinase receptors. Thus, the common therapeutic approach for GIST therapy (including metastatic, recurrent and non-resectable forms) is based on inhibiton of activities of receptor tyrosine kinases indicated above by corresponding receptor tyrosine kinase inhibitors, including first-line therapeutic agent imatinib mesylate – Gleevec. Despite of high efficacy of IM-based therapy, most of GIST patients acquire resistance to this receptor tyrosine kinase inhibitor, which in turn requires second-, third- and fourth-line therapies. The review also describes the common molecular and genetic variants of GIST and the mechanisms of primary and secondary GIST resistance to the targeted-based therapies. In addition, the role of immune microenvironment in GIST and its relationship with tumor’s mutational burden are discussed in detail, thereby illustrating the immunotherapy as one of the attractive future directions for GIST therapy. Lastly, the manuscript provides the information about the ongoing clinical trials of GIST immunotherapy.

Programmed cell death protein ligand‐1 (PD‐L1) expression in non‐small cell lung cancer (NSCLC) tumors guides treatment selection. PD‐L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD‐L1 and marker of proliferation Ki‐67 (Ki67; also known as MKI67) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD‐L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post‐first cycle, post‐third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD‐L1high/low/medium/negative and Ki67+ or Ki67−. CTC evaluation revealed a significant increase in the PD‐L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD‐L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD‐L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression‐free survival (PFS) was longer in patients with decreased total and PD‐L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD‐L1+ patients presenting a high Ki67 index (% Ki67+ CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD‐L1+ patients harboring Ki67+ CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD‐L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy.

Simple Summary: According to the Society for Immunotherapy of Cancer, primary resistance to immune checkpoint inhibitor (ICI) treatment is defined as progression of disease within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy. We evaluated factors predictive of primary resistance to ICI monotherapy in 108 advanced non-small-cell lung cancer patients. The prevalence of primary resistance was 54.6%. The majority of patients were male, smokers, received pembrolizumab and had adenocarcinoma histology. We found that female gender, an elevated neutrophil-to-lymphocyte ratio of ≥3 at 6 weeks and a later line of immunotherapy treatment (≥2 lines) were key factors in predicting primary resistance to ICI monotherapy in advanced NSCLC. Introduction: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). Method: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. Results: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. Conclusions: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Programmed cell death protein ligand‐1 (PD‐L1) expression in non‐small cell lung cancer (NSCLC) tumors guides treatment selection. PD‐L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD‐L1 and marker of proliferation Ki‐67 (Ki67; also known as MKI67) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD‐L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post‐first cycle, post‐third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD‐L1high/low/medium/negative and Ki67+ or Ki67−. CTC evaluation revealed a significant increase in the PD‐L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD‐L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD‐L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression‐free survival (PFS) was longer in patients with decreased total and PD‐L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD‐L1+ patients presenting a high Ki67 index (% Ki67+ CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD‐L1+ patients harboring Ki67+ CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD‐L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have contributed significantly to the treatment of various types of cancer, including skin cancer. However, not all patients respond; some patients do not respond at all (primary resistance), while others experience recurrence after the initial response (acquired resistance). Therefore, overcoming ICI resistance is an urgent priority. Numerous ICI resistance mechanisms have been reported. They are seemingly quite complex, varying from patient to patient. However, most involve T‐cell activation processes, especially in the tumor microenvironment (TME). ICIs exert their effects in the TME by reactivating suppressed T cells through inhibition of immune checkpoint molecules, such as cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and programmed cell death protein 1 (PD‐1). Thus, this review focuses on the resistance mechanisms based on the T‐cell activation process. Here, we classify the main mechanisms of ICI resistance into three categories based on (1) antigen recognition, (2) T‐cell migration and infiltration, and (3) effector functions of T cells. By identifying and understanding these resistance mechanisms individually, including unknown mechanisms, we seek to contribute to the development of novel treatments to overcome ICI resistance. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. β-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P =.026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients. [ABSTRACT FROM AUTHOR]

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC. [ABSTRACT FROM AUTHOR]

The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment. [ABSTRACT FROM AUTHOR]

• Advanced lung adenocarcinoma patient with EGFR mutations often experience resistance. • Primary resistance leads to a worse response for patients. • Offer new insights to provide effective precise treatments for patients harboring sensitizing EGFR mutation. Advanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies. A retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal). The most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G , STK11 , EPAS1 , RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24–76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68–78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57–56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67–54.28, p = 0.011) were significantly associated with shorter PFS. The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations. [ABSTRACT FROM AUTHOR]

Empirical treatment needs to be supported by regional data, but knowledge of interregional differences is currently lacking in China. This study aimed to summarize and map the primary and secondary antibiotic resistance of Helicobacter pylori in different regions of mainland China. PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure and Wanfang databases were systematically reviewed for studies published between 1 January 2000 and 15 July 2023. Data related to primary and secondary H. pylori antibiotic resistance rates were included. Random-effects models were used to synthesize the pooled resistance rates. Ultimately, 74 studies were included in the final analysis. A total of 16 provinces reported resistance data. The overall resistance rates of H. pylori in mainland China were 30.72% (95% CI 27.53%–33.99%) to clarithromycin, 70.14% (95% CI 29.53%–37.46%) to metronidazole and 32.98% (95% CI 28.73%–37.37%) to levofloxacin; for amoxicillin, tetracycline, and furazolidone, the rates were 2.41% (95% CI 1.43%–3.60%), 2.53% (95% CI 1.19%–4.28%) and 1.54% (95% CI 0.28%–3.62%), respectively. Spatial and temporal differences were observed. The resistance rates increased after treatment failure; however, secondary resistance to amoxicillin, tetracycline and furazolidone were still low across the vast majority of study regions. Surveillance of the updated prevalence of antibiotic resistance of H. pylori for different regions is warranted, which should factor into clinical decision making and guideline recommendations. [Display omitted] [ABSTRACT FROM AUTHOR]

Anti-PD-1 immunotherapy has been extensively used in treatment of patients with advanced metastatic renal cell carcinoma (mRCC). Several prospective clinical trials showed that the combined treatment of anti-PD-1 antibody plus lenvatinib, a potent receptor tyrosine kinase inhibitor (TKI), exhibited high response rate compared with single-agent sunitinib. However, whether the patients with primary resistance to PD-1 blockade could benefit from the addition of lenvatinib is still unclear. Herein, we reported a patient with mRCC who was primary resistant to pembrolizumab and achieved a durable complete response after a short-term treatment with lenvatinib. This case report indicates that the patients with primary resistance to anti-PD-1 therapy could benefit from the shortterm lenvatinib in combination with anti-PD-1 therapy, and provides a useful paradigm worthy of establishing a clinical trial for mRCC patients with primary resistance to anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Resistance to antiangiogenic therapy represents a challenge in the therapeutic approach for hepatocellular carcinoma (HCC). The advent of immune checkpoint inhibitors (ICIs) seems to be a solution to this issue; however, other gaps have emerged since they have only been shown to provide benefit in approximately 20% of patients. Combination strategies have introduced in clinical development to overcome this issue. This review deals with the resistance to antiangiogenic drugs by focusing on two protagonists, the tumor microenvironment and vascular normalization, to offer possible overcoming strategies. Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms. [ABSTRACT FROM AUTHOR]

• Resistance mechanisms for immune checkpoint inhibitors (ICIs) were explored. • The tumor immune microenvironment in advanced NSCLC was evaluated in detail by a single-cell spatial profiling with 16 or 17-color multiplex IHC. • Primary ICI resistance was associated with a lack of neoantigen-specific CD8+ TILs. • Acquired resistance was related to MDSC infiltration, neoepitope loss, and other features. Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non–small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)–based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death–1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary. [ABSTRACT FROM AUTHOR]

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Simple Summary: Immune checkpoint inhibitors (ICIs) had been explored extensively in patients affected by unresectable hepatocellular carcinoma. These agents were expected to be the keystones of the disease's first-line treatment because they were theoretically able to revert the immune suppressive tumor microenvironment of the cancerous liver, and because of their manageable safety profile. However, when used as monotherapies, they showed important activity and efficacy limitations. In this mini-review, we summarize the characteristics of the different ICIs-based regimens which constitute the present gold standard of first-line treatment, then, moving from their shortcomings, we discuss the rationale supporting the strategies currently under investigation: systemic triplets and new paradigms of immune-therapeutic agents such as CAR-T and vaccines. Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the "doublets strategy" still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises. [ABSTRACT FROM AUTHOR]

Aim: Understanding the prevalence of antibiotic resistance can provide reliable information for selecting treatment options. The goal of this meta-analysis was to observe the primary antibiotic resistance of Helicobacter pylori (H. pylori) in different regions and time periods of China. Method: We searched PubMed, EMBASE, Chinese Biomedical databases and the China National Knowledge Infrastructure from inception to 20 February 2022. Data on the prevalence of H. pylori primary resistance at various time points were included. A random-effect model was established to calculate the pooled antibiotic resistance. Results: In total, 2150 articles were searched, with 70 meeting the inclusion criteria. The resistance to clarithromycin, metronidazole, levofloxacin amoxicillin, tetracycline and furazolidone in 2016–2020 were 34% (95% CI: 30–39%), 78% (95% CI: 73–84%), 35% (95% CI: 30–40%), 3% (95% CI: 1–5%), 2% (95%CI: 1–4%) and 1% (95% CI: 0–4%), respectively. Clarithromycin showed regional difference, as the resistance was higher in northern (37%, 95% CI: 32–41%) and western China (35%, 95% CI: 17–54%) than that in southern (24%, 95% CI: 17–32%) and eastern China (24%, 95% CI: 20–28%). Conclusion: The resistance of H. pylori to clarithromycin and metronidazole was high and increased over time, whereas resistance to levofloxacin, amoxicillin, tetracycline and furazolidone remained stable. [ABSTRACT FROM AUTHOR]

Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC. [ABSTRACT FROM AUTHOR]

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC. [ABSTRACT FROM AUTHOR]

Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

Background: Immunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes. Methods: This is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan–Meier method and the Cox proportional hazards model. Results: Twenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median. Conclusions: In this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) patients benefit from EGFR tyrosine kinase inhibitors (TKIs), while some patients demonstrate a resistance to EGFR‐TKIs. In the case reported here, the NSCLC patient harboring an EGFR‐sensitive mutation and YES1 amplification was treated with afatinib as first‐line therapy, but was found to have progressive disease four weeks later. During subsequent chemotherapy, this patient's disease progressed rapidly. Mechanisms of primary resistance to EGFR‐TKIs remain unclear. This case suggested that YES1 amplification might be associated with primary resistance to EGFR‐TKIs and YES1 amplification might be a negative predictor of EGFR‐TKI treatment in NSCLC patients harboring EGFR sensitive mutations.

Abstract Introduction Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20–30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. Methods Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. Results Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. Conclusion MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

Immunotherapy is a rapidly evolving treatment paradigm that holds promise to provide long-lasting survival benefits for patients with cancer. This promise, however, remains unfulfilled for the majority of patients with gastrointestinal (GI) cancers, as significant limitations in efficacy exist with immune checkpoint inhibitors (ICIs) in this disease group. A plethora of novel combination treatment strategies are currently being investigated in various clinical trials to make them more efficacious as our understanding of molecular mechanisms mediating resistance to immunotherapy advances. In this article, we summarize the current status of immune checkpoint blockade in GI cancers and discuss the biological rationales that underlie the emerging treatment strategies being tested in ongoing clinical trials in combination with ICIs. We also highlight the promising early results from these strategies and provide future perspectives on enhancing response to immunotherapy for patients with GI cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. As the most prevalent molecular mutation subtypes in non-small cell lung cancer (NSCLC), EGFR-TKIs are currently a standard first-line therapy for targeting the mutated EGFR in advanced NSCLC patients. However, 20-30% of this subset of patients shows primary resistance to EGFR-TKIs. Patients with co-mutations of EGFR and several other genes have a poor response to EGFR-TKIs, whereas the prognostic and predictive significance of EGFR/TP53 co-mutation in NSCLC patients remains controversial. Meanwhile, little is known about how to choose an optimal therapeutic strategy for this subset of patients. Presently, no drugs targeting TP53 mutations are available on the market, and some p53 protein activators are in the early stage of clinical trials. A combination of EGFR-TKIs with antiangiogenic agents or chemotherapy or other agents might be a more appropriate strategy to tackle the problem. In this review, we describe the prognostic and predictive value of EGFR/TP53 co-mutation in NSCLC patients, investigate the mechanisms of this co-mutation affecting the response to EGFR-TKIs, and further explore optimal regimens effectively to prolong the survival time of the NSCLC patients harboring this co-mutation.

BackgroundImmunotherapy has become the standard of care for non-small cell lung cancer (NSCLC) patients. Some patients experience primary resistance to immunotherapy. Currently, we lack a marker of resistance to immunotherapy. Myeloid-derived suppressive-like cells (MDSCs) can reduce tumor response rate and survival outcomes.MethodsThis is an exploratory prospective observational study on metastatic NSCLC patients starting immunotherapy. Baseline peripheral blood samples were collected. Monocytic (M)-MDSCs were analyzed by flow cytometry. The main clinical outcomes were tumor response, progression-free survival (PFS), and overall survival (OS). The association between MDSC levels and tumor response was assessed. The association of PFS with OS was investigated using the Kaplan–Meier method and the Cox proportional hazards model.ResultsTwenty-two patients were included. The median M-MDSC value was higher in patients with progressive disease than patients with stable disease or partial response, p = 0.045. The median MDSC value in the overall population was 1.9. We found worse PFS (HR = 2.51; p = 0.046) and OS (HR = 2.68; p = 0.042) in patients with M-MDSC values higher than the median.ConclusionsIn this exploratory analysis, high M-MDSC levels are strongly associated with primary resistance to immunotherapy. If validated in larger studies, MDSC levels in blood samples could help to select NSCLC patients for higher benefit from immunotherapy.

To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF - mutated and microsatellite stable (MSS) metastatic colorectal cancer. In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6–20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3–7.29] versus 3 [IQR, 1.26–3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07–4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02–4.81, P = 0.044). Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF -mutated mCRC deserves prospective validation. • Primary resistance to BRAF inhibitors in BRAF -mutated metastatic colorectal cancer (mCRC) is as high as 25%. • No established biomarkers predict primary resistance. • TMB reflects elevated intra-tumour heterogeneity in microsatellite stable (MSS) tumours. • Higher TMB is associated with primary resistance to EGFR/BRAF blockade in MSS mCRC. • Higher TMB predicts inferior PFS and OS following EGFR/BRAF blockade in MSS mCRC. [ABSTRACT FROM AUTHOR]

In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors—primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)—and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model.

Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC.

In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors—primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)—and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model. [ABSTRACT FROM AUTHOR]

Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion: The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy. [ABSTRACT FROM AUTHOR]

Sorafenib is the first-line therapeutic option for advanced hepatocellular carcinoma (HCC). Many patients exhibit a primary resistance (PR) response after initial treatment. In previous studies, compared to acquired resistance, the mechanism of PR is unclear. The present study aimed to evaluate the response of patient samples to sorafenib by patient-derived xenograft (PDX) models, and the differences at the transcriptome level between the sorafenib PR group and the sorafenib sensitive group were analyzed by single-cell sequencing technology. A specific cell cluster may be differentiated by the liver bud hepatic cells, and the JUN transcription factors in this cell cluster were highly activated. The albumin is secreted by other cell clusters, and the cluster stimulates the FcRn complex receptor to activate the HIF pathway and cell proliferation, resulting in a poor response to sorafenib. These findings are validated by both cell communication analysis and experiments. Thus, the current studies provided a novel approach for the treatment of sorafenib-resistant HCC. [ABSTRACT FROM AUTHOR]

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK -positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations. [ABSTRACT FROM AUTHOR]

EGFR‐activating mutations have been recognized as the most important predictor of response to EGFR‐tyrosine kinase inhibitors (TKIs); however, 20–30% of patients harboring EGFR‐activating mutations show poor responses. The mechanisms of such EGFR‐TKI primary resistance are still poorly understood. In our case, a non‐small cell lung cancer patient developed intrinsic EGFR‐TKI resistance and was then confirmed to simultaneously harbor an L858R mutation and ROS1 rearrangement. Salvage chemotherapy plus Endostar showed enduring therapeutic effects, achieving a disease‐free survival period of 24 months and overall survival of 30 months. This suggests that co‐activation of different oncogenic signal pathways might be a potential mechanism of EGFR‐TKI primary resistance. Chemotherapy combined with anti‐angiogenesis should be considered an important salvage strategy. Further studies are warranted to verify these findings and explore the underlying mechanisms involved.

Background Resistance to clarithromycin and levofloxacin in Helicobacter pylori which resulted in treatment failures has become a major challenge for physicians worldwide. The resistance is mainly mediated by mutations in a specific domain of the 23S rRNA, gyrA and gyrB genes for clarithromycin and levofloxacin respectively. Hence in this study, we aimed to investigate the current status of H. pylori resistance in our hospital to these two antibiotics based on the molecular approach. Materials and Methods Gastric biopsy samples were obtained from treatment-naïve patients. Bacterial genomic DNA was extracted using a commercial kit and continued with DNA amplification using polymerase chain reaction (PCR) with specific primers. The PCR amplicons were subjected to sequencing on 23S rRNA gene targeting nucleotide positions at 2,146, 2,147, 2,186 and amino acids at gyrA positions 87 and 91 and gyrB positions 436, 438, 481, 484 to investigate the possible mutations or polymorphisms of genes that lead to clarithromycin and levofloxacin resistance respectively. Results Sixty-one urease-positive gastric biopsy samples were studied. The findings revealed the primary resistance rates to clarithromycin was 14.8% and to levofloxacin was 3.3% in our current scenario based on detection of reported resistance-related mutations of A2147G and D91N in 23S rRNA and gyrA genes, respectively. Interestingly, we found a high rate of silent mutations of the gyrA codon 87Asn (32.8%, 20/61) and two polymorphisms of the gyrB D481E (16.4%, 10/61) and R484K (21.3%, 13/61). The role of these polymorphisms in gyrB remained to be elucidated whether the levels of levofloxacin resistance are related to the position/amino acid. Conclusion The primary resistance rate of H. pylori to clarithromycin has increased compared to the previous report in Malaysia. Therefore, molecular screening could aid and is important for the selection of antibiotics for H. pylori eradication therapies.

No data concerning antiretroviral drug's (ARV) primary resistance mutation rates in Chad are available. We retrospectively analysed frozen-stored dried blood spot samples that were collected from 48 Chadian human immunodeficiency virus (HIV)-1 seropositive patients naïve of ARV. HIV-1 protease and reverse transcriptase genes were successfully sequenced for 24 (60.0%) of the 40 patients displaying a viral load > 1000 copies/ml. Seven (29.2%) displayed mutations conferring resistance against one or more classes of ARV. We evidenced high levels of primary ARV resistance mutations in Chad, but lower than those observed in patients with failure to first-line ARV. [ABSTRACT FROM AUTHOR]