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Background: Osimertinib is approved as a standard treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation by FDA. However, the mechanisms of resistance for nearly half of patients after osimertinib progression are still unknown, and the optimal therapies for these patients are still controversial. In this retrospective study, we compared efficacy and safety between immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab in NSCLC patients after osimertinib progression with unknown resistance mechanisms., Methods: Advanced NSCLC patients with unknown resistance mechanisms after osimertinib progression were retrospectively reviewed and divided into immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab treatment groups according to the treatment they received after osimertinib progression. Clinicopathological features, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between groups., Results: A total of 121 patients were enrolled in this study, 22 in the immunotherapy + chemotherapy group, 72 in the chemotherapy group, and 27 in the osimertinib + bevacizumab group. The ORR was much higher in the immunotherapy + chemotherapy group compared with chemotherapy or osimertinib + bevacizumab group (55.56% vs. 14.81% vs. 0% in patients after progression on 1st line osimertinib treatment; 30.77% vs. 6.67% vs. 13.33% in patients after progression on 2nd/3rd line osimertinib treatment). Median PFS was also significantly longer in the immunotherapy + chemotherapy group compared with other groups (8.2 months vs. 4.0 months vs. 6.0 months in all patients, p = 0.0066). The median OS did not reach remarkable difference among groups, although osimertinib + bevacizumab group had a numerically longer median OS (37.0 months vs. 37.0 months vs. 47.6 months in all patients, p = 0.6357). Compared with immunotherapy + chemotherapy and chemotherapy, treatment-related adverse events (AEs) of osimertinib + bevacizumab were milder, especially in AEs related to gastrointestinal and bone marrow suppression., Conclusion: Our study provides clinical evidence that NSCLC patients after osimertinib progression with unknown resistance mechanisms may benefit from immunotherapy + chemotherapy, with higher ORR and longer PFS compared with osimertinib + bevacizumab or chemotherapy groups. Osimertinib + bevacizumab treatment was also an optional option for patients because OS was numerically longer and safer in this group., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Patients with non-small cell lung cancer (NSCLC) are easily resistant to first-line chemotherapy with paclitaxel (PTX) or carboplatin (CBP). N 6 -methyladenosine (m 6 A) methyltransferase-like 3 (METTL3) has crucial functions in m 6 A modification and tumorigenesis. However, its role in chemoresistance of NSCLC is still elusive. Here, we demonstrated that METTL3 inhibitor STM2457 significantly reduced the IC 50 values of PTX or CBP in NSCLC cells, and they showed a synergistic effect. Comparing with monotherapy, a combination of STM2457 and PTX or CBP exhibited more potent in vitro and in vivo anti-tumor efficacy. In addition, we found that ATP binding cassette subfamily C member 2 (ABCC2) was responsively elevated in cytomembrane after PTX or CBP treatment, and targeting METTL3 could reverse this effect. Mechanistically, targeting METTL3 decreased the m 6 A modification of ABCC2 mRNA and accelerated its mRNA degradation. Further studies revealed that YTHDF1 could bind and stabilize the m 6 A-modified mRNA of ABCC2 , while YTHDF1 knockdown promoted it mRNA degradation. These results, taken together, demonstrate that targeting METTL3 enhances the sensitivity of NSCLC cells to PTX or CBP by decreasing the cytomembrane-localized ABCC2 in an m 6 A-YTHDF1-dependent manner, and suggest that METTL3 may be a potential therapeutic target for acquired resistance to PTX or CBP in NSCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The third-generation EGFR-TKI osimertinib is widely used in EGFR-mutated positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. The currently known mechanisms only explain resistance in a small proportion of patients. For most patients, the mechanism of osimertinib resistance is still unclear, especially for EGFR-independent resistance. Herein, we thoroughly investigated the novel mechanism of osimertinib resistance and treatment strategies. We identified that ST3GAL4, a sialyltransferase, catalyzes terminal glycan sialylation of receptor protein tyrosine kinases, which induces acquired resistance to osimertinib in vitro and in vivo. In addition, ST3GAL4 is generally overexpressed in osimertinib-resistant patients with unknown resistance mechanisms. ST3GAL4 modifies MET glycosylation on N785 with sialylation, which antagonizes K48-related ubiquitin-dependent MET degradation and subsequently activates MET and its downstream proliferation signaling pathways. Meanwhile, ST3GAL4 knockdown or inhibition by brigatinib resensitizes resistant non-small cell lung cancer cells to osimertinib in vitro and in vivo This study suggests that ST3GAL4 can induce acquired resistance to osimertinib, which may be an important EGFR-independent resistance mechanism Furthermore, targeting ST3GAL4 with brigatinib provides new strategies to overcome osimertinib resistance., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study aimed to develop and validate radiomics and deep learning (DL) signatures for predicting distal metastasis (DM) of non-small cell lung cancer (NSCLC) in low-dose computed tomography (LDCT)., Methods: Images and clinical data were retrospectively collected for 381 NSCLC patients and prospectively collected for 114 patients at the Fifth Affiliated Hospital of Sun Yat-Sen University. Additionally, we enrolled 179 patients from the Jiangmen Central Hospital to externally validate the signatures. Machine-learning algorithms were employed to develop radiomics signature while the DL signature was developed using neural architecture search. The diagnostic efficiency was primarily quantified with the area under receiver operating characteristic curve (AUC). We interpreted the reasoning process of the radiomics signature and DL signature by radiomics voxel mapping and attention weight tracking., Results: A total of 674 patients with pathologically-confirmed NSCLC were included from two institutions, with 143 of them having DM. The radiomics signature achieved AUCs of 0.885, 0.854, and 0.733 in the internal validation, prospective validation, and external validation while those for DL signature were 0.893, 0.786, and 0.780. The proposed signatures achieved a promising performance in predicting the DM of NSCLC and outperformed the approaches proposed in previous studies. Interpretability analysis revealed that both radiomics and DL signatures could detect the variations among voxels inside tumors, which helped in identifying the DM of NSCLC., Conclusions: Our study demonstrates the potential of LDCT-based radiomics and DL signatures for predicting DM in NSCLC. These signatures could help improve lung cancer screening regarding further diagnostic tests and treatment strategies., (© 2024. Italian Society of Medical Radiology.)

Objective: Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited., Methods: We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our analysis specifically focused on the acquired changes to the KRAS gene., Results: Among the 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations who experienced resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy, 14 individuals (4.3%) developed resistance due to acquired KRAS alterations. Of these 14 patients, 10 cases (71.4%) were due to KRAS missense mutations, 1 case (7.2%) was due to KRAS gene fusion and 3 cases (21.4%) were due to KRAS amplification. Notably, we identified one newly demonstrated KRAS gene fusion (KRAS and LMNTD1), one KRAS G13D and one KRAS K117N. The emergence of acquired KRAS alterations was often accompanied by novel mutations and high tumor mutation burden, with TP53, CNKN2A, PIK3CA, MYC, STK11, CDK4, BRCA2 and ERBB2 being the most frequently observed concurrent mutations. The median progression-free survival and overall survival for the 14 patients were 5.2 and 7.3 months, respectively. Acquired KRAS missense variants were associated with significantly worse progression-free survival compared with other KRAS variant subtypes (P < 0.028)., Conclusions: This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The clinical outcome of resectable non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant chemoimmunotherapy is good but varies greatly. In addition, the pathological response after neoadjuvant chemoimmunotherapy is significantly associated with survival outcomes. The aim of this retrospective study was to identify which population of patients with locally advanced and oligometastatic NSCLC has a favorable pathological response after neoadjuvant chemoimmunotherapy. NSCLC patients treated with neoadjuvant chemoimmunotherapy were enrolled between February 2018 and April 2022. Data on clinicopathological features were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment puncture specimens and surgically resected specimens. In total, 29 patients with stages III and IV locally advanced or oligometastatic NSCLC who received neoadjuvant chemoimmunotherapy and R0 resection were enrolled. The results showed that 55% (16/29) of patients had a major pathological response (MPR) and 41% (12/29) of patients had a complete pathological response (pCR). In the stroma area of the pre-treatment specimen, the higher infiltration of CD3 + PD-L1 + tumor-infiltrating lymphocytes (TILs) and the lower infiltration of CD4 + and CD4 + FOXP3 + TILs were more likely to appear in patients with pCR. However, in the tumor area, the higher infiltration of CD8 + TILs was more likely to appear in patients with non-MPR. In the post-treatment specimen, we found increased infiltration of CD3 + CD8 + , CD8 + GZMB + , and CD8 + CD69 + TILs and decreased infiltration of PD-1 + TILs both in the stroma and tumor areas. Neoadjuvant chemoimmunotherapy achieved an MPR rate of 55% and induced greater immune infiltration. In addition, we observed that the baseline TILs and their spatial distribution correlate to the pathological response., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Plasma and tissue biopsy have both used for targeting actionable driver gene mutations in lung cancer, whose concordance is imperfect. A reliable method to predict the concordance is urgently needed to ease clinical application., Methods: A total of 1012 plasma samples, including 519 with paired-tissue biopsy samples, derived from lung adenocarcinoma patients were retrospectively enrolled. We assessed the associations of several clinicopathological characteristics and serum tumor markers with the concordance between plasma and tissue biopsies., Results: When carcinoembryonic antigen (CEA) levels were higher than thresholds of 15.01 ng/ml and 51.15 ng/ml, the positive predictive value of concordance reached 90% and 95%, respectively. When CEA levels were lower than thresholds of 5.19 ng/ml and 3.26 ng/mL, the negative predictive value of concordance reached 45% and 50%. The performance of CYFRA21-1 in predicting concordance was similar but inferior to CEA (AUC: 0.727 vs. 0.741, p = 0.633). The performance of CEA combined with CYFRA21-1 in predicting the concordance was similar to that of the combination of independent factors derived from the LASSO regression model (AUC: 0.796 vs. 0.818, p = 0.067). CEA (r = 0.47, p < 0.01) and CYFRA21-1 levels (r = 0.45, p < 0.05) were significantly correlated with the maximum variant allele frequency, respectively., Conclusions: CEA combined with CYFRA21-1 could effectively predict the concordance between plasma and tissue biopsies, which could be used for evaluating the priority of plasma and tissue biopsies for gene testing to timely guide clinical applications in advanced lung adenocarcinoma patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Circulating tumor DNA (ctDNA) has made a breakthrough as an early biomarker in operable early-stage cancer patients. However, the function of ctDNA combined with cell-free DNA (cfDNA) as a predictor in advanced non-small cell lung cancer (NSCLC) remains unknown. Here, we explored its potential as a biomarker for predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced NSCLC., Methods: A retrospective analysis was undertaken. Plasma collected from 51 patients with advanced NSCLC prior to and serially after starting treatment with EGFR-TKIs was analyzed by next-generation sequencing (NGS). The performance of ctDNA, cfDNA, and combining ctDNA with cfDNA were evaluated for their ability to predict survival outcomes., Results: Patients with early undetectable ctDNA and increasing cfDNA had a markedly better progression-free survival (PFS) (p < 0.001) and overall survival (OS) (p = 0.001) than those with early detectable ctDNA and decreasing cfDNA. Patients with early ctDNA clearance were more likely to have the ctDNA persistent clearance (p = 0.006). The early clearance rate of ctDNA in the normal carcinoembryonic antigen (CEA) group was significantly higher than in the low and high groups (p = 0.028). Patients with greater CEA decline had a higher early clearance rate of ctDNA than those with minor CEA change (p = 0.016)., Conclusions: We based this study on ctDNA and cfDNA, explored its prognostic predictive ability, and combined CEA to monitor EGFR-TKI efficacy. This study may provide new perspectives and insights into the precise treatment strategies for NSCLC patients., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The prognosis of non-small-cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is poor. Detection of cell-free DNA (cfDNA) by next generation sequencing (NGS) in cerebrospinal fluid (CSF) may facilitate diagnosis of LM and identification of drug resistance mechanisms, yet its clinical use needs to be further verified., Methods: We performed a retrospective cohort study to assess the genetic profiles of paired CSF and plasma samples in lung cancer patients with LM. Of 17 patients screened, a total of 14 patients with LM and paired NGS tests were enrolled., Results: All patients harbor driver gene mutations, including 12 epidermal growth factor receptor (EGFR) activating mutations, 1 anaplastic lymphoma kinase (ALK) rearrangement, and 1 ROS-1 fusion. Genetic mutations were detected in CSF cfDNA from 92.9% patients (13/14), which was significantly higher than that from the plasma (9/14, 64.2%). The mutations were highly divergent between CSF and plasma cfDNA, with a concordance rate of 24.38% and 10 mutations shared by the two media. CSF cfDNA could also benefit the analysis of resistance mechanisms to targeted therapies. In five patients who experienced progression on 1st or 2nd generation EGFR-tyrosine kinase inhibitors (TKIs), RB1 mutation, and amplification of MET and EGFR were detected in CSF cfDNA only. In eight patients with LM progression on osimertinib resistance, EGFR amplification was detected in CSF cfDNA from four patients, whereas no CNVs were detected in the matched plasma samples., Conclusions: In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib., (© 2022. The Author(s).)

Background: Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK + NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK + NSCLC cells to crizotinib requires further investigation., Methods: The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis., Results: ALK + NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK - NSCLC cells. Long-term exposure to crizotinib could decrease the sensitivity of ALK + NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases II (HK2). Crizotinib in combination with glycolysis inhibitor 2-deoxy-D-glucose (2DG) synergistically inhibited proliferation, glycolysis, colony formation and invasion ability of ALK + NSCLC cells. 2DG sensitization crizotinib might be associated with the inhibition of HK2-mediated glycolysis and P-ALK/AKT/mTOR signaling pathway in H3122 and H2228 cells., Conclusions: These results indicate that HK2-mediated glycolysis plays a crucial role in the increased tolerance of ALK + NSCLC cells to crizotinib. 2DG may sensitize ALK + NSCLC to crizotinib via suppression of HK2-mediated glycolysis and the AKT/mTOR signaling pathway., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Acquired resistance to osimertinib mediated by EGFR cis-C797S is now a growing challenge. No effective treatment strategy is currently available to overcome cis-C797S-mediated resistance., Methods: In this retrospective cohort study, 15 patients with advanced lung adenocarcinoma and EGFR-activating mutation, T790M, and cis-C797S after osimertinib progression were identified by targeted next-generation sequencing. Five of these patients received a combined therapy of brigatinib and cetuximab, and 10 patients received cisplatin-based doublet chemotherapy., Results: Among the five patients who were positive for EGFR 19del-T790M-cis-C797S mutations, and who received brigatinib and cetuximab combination therapy, three patients achieved partial response, and two had stable disease, resulting in an overall objective response rate of 60% and disease control rate of 100%. Among the 10 patients who were positive for EGFR 19del or L858R-T790M-cis-C797S mutations and received chemotherapy, only one patient achieved partial response, five had stable disease, and the other four did not benefit from chemotherapy, resulting in an overall objective response rate and disease control rate of 10% and 60%, respectively. The median progression-free survival of patients who received combined targeted therapy was 14 months, and 3 months for those treated with chemotherapy. No grade III to IV adverse events were observed in any patient., Conclusions: Our retrospective study provides clinical evidence that a combined targeted therapy of brigatinib and cetuximab could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients who acquire EGFR T790M-cis-C797S-mediated resistance to osimertinib., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Osimertinib, a third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), provides marked clinical benefit for patients with EGFR-activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two 'special' patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib-resistant non-small-cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib-resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC-9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression-free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib-resistant lung cancer cells through promoting Bim-dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

Purpose: Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm)., Patients and Methods: A total of 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis., Results: The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0-52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6-52.7) with gefitinib plus placebo ( P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%)., Conclusions: Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC., (©2019 American Association for Cancer Research.)

Introduction: The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib is a promising therapeutic option for patients with advanced non-small-cell lung cancer (NSCLC) in second-line or first-line treatment because of its applications in selectively inhibiting EGFR T790M and EGFR-tyrosine kinase inhibitor sensitizing mutations. However, the activation of autophagy associated with osimertinib treatment may play a protective role in NSCLC cells injury induced by osimertinib., Objectives: The aim of the present study was to study the effects of the osimertinib-induced autophagy in NSCLC cells and whether metformin modulates the autophagy and enhances osimertinib sensitivity., Methods: The effect of metformin on enhancing osimertinib sensitivity was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, colony formation assay, invasion assay, flow cytometry analysis, western blot analysis and siRNA technique., Results: In the present study, we confirmed that osimertinib induced pro-survival autophagy in H1975 and PC-9GR cells, and metformin further sensitized H1975 and PC-9GR cells to osimertinib via inhibiting autophagy. The potential mechanism was that the continual activation of AMPK induced by metformin could inhibit autophagy in a time-dependent manner., Conclusion: Metformin inhibited autophagy and enhanced osimertinib sensitivity via inducing AMPK activation in a time-dependent manner., (© 2019 John Wiley & Sons Ltd.)

Background: Immune-therapy with anti-PD1 inhibitors, such as pembrolizumab, is revolutionizing the treatment of non-small cell lung cancers (NSCLC). However, identifying patients for the potential therapeutic response and predicting therapy resistance and early relapse remains a challenge., Methods: Between 2016 and 2018, 60 patients were treated with pembrolizumab, among who 12 NSCLC patients had both baseline (before treatment) and serial (on treatment) periodical circulating tumor DNA (ctDNA) samples. Those samples were sequenced on a 329 pan cancer-related gene panel. Analyses of tumor burden, blood tumor mutational burden (bTMB), maximum somatic allele frequency (MSAF), and tumor clonal structure were performed in association with clinical response. Candidate resistance mutations involved in relapse and metastases were further investigated., Results: ctDNA was detected and mutational profiling was performed for each patient. Those with a high baseline bTMB level showed significantly improved progression-free survival (PFS) after pembrolizumab treatment. Tumor burden and therapeutic response significantly correlated with the MSAF instead of the bTMB. Clone analysis detected tumor progression about 2-4 months ahead of computed tomography (CT) scan. One mutation in gene PTCH1 (Protein patched homolog 1) and two acquired anti-PD1 candidate resistance mutations of gene B2M (β2 microglobulin) were identified in association with distant metastasis. The evolutionary tree of a representative patient was also described., Conclusion: This pilot study showed that MSAF could be another good indicator of therapeutic response, and clonal analysis could be clinically useful in monitoring clonal dynamics and detecting remote metastasis and early relapse., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Osimertinib, a third-generation epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI), shows great efficacy in EGFR-mutant non-small cell lung cancer (NSCLC); however, the resistance is inevitable. Osimertinib induces autophagy in NSCLC cells, but the role of autophagy in osimertinib resistance is not clear. We discovered that enhanced autophagy is associated with osimertinib resistance in vitro and in vivo. Inhibition of autophagy enhanced osimertinib cytotoxicity in both osimertinib-resistant and sensitive cells. Moreover, osimertinib-resistant cells exhibited stem cell-like properties, whereas autophagy inhibition decreased the stemness by downregulating the expression of SOX2 and ALDH1A1. Further, we found that knockdown of Beclin-1 inhibited the stem cell-like properties and restored osimertinib cytotoxicity. Osimertinib combined with chloroquine inhibited tumor growth more effectively than alone in xenograft mice. These results reveal that autophagy plays an adverse role in osimertinib cytotoxicity through inducing stem cell-like properties. Combination therapy of EGFR-TKI and autophagy inhibitor could provide a promising strategy to improve osimertinib cytotoxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Despite the impressive efficacy of crizotinib for the treatment of ALK-positive non-small cell lung cancer, patients invariably develop therapeutic resistance. Suppression of the IGF-1R signaling pathway may abrogate this acquired mechanism of drug resistance to crizotinib. Metformin, a widely used antidiabetic agent, may reverse crizotinib resistance through inhibition of IGF-1R signaling., Results: The present study revealed that metformin effectively increased the sensitivity of both crizotinib-sensitive and -resistant non-small cell lung cancer cells to crizotinib, as evidenced by decreased proliferation and invasion and enhanced apoptosis. Metformin reduced IGF-1R signaling activation in crizotinib-resistant cells. Furthermore, the addition of IGF-1 to crizotinib-sensitive H2228 cells induced crizotinib resistance, which was overcome by metformin., Experimental Design: The effects of metformin to reverse crizotinib resistance were examined in vitro by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), invasion assay, ki67 incorporation assay, flow cytometry analysis, Western blot analysis, and colony-forming assay., Conclusions: Metformin may be used in combination with crizotinib in ALK+ NSCLC patients to overcome crizotinib resistance and prolong survival., Competing Interests: The authors declare no potential conflicts of interest.

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), leading to the largest number of cancer-related deaths worldwide. The high mortality rate may be attributed to the delay of detection. Therefore, it is of great importance to explore the mechanism of lung adenocarcinoma metastasis and the strategy to block metastasis of the disease. We searched and downloaded mRNA and miRNA expression data and clinical data from The Cancer Genome Atlas (TCGA) database to identify differences in mRNA and miRNA expression of primary tumor tissues from lung adenocarcinoma that did and did not metastasize. In addition, combined with bioinformatic prediction, we constructed an miRNA-target gene regulatory network. Finally, we employed RT-qPCR to validate the bioinformatic approach by determining the expression of 10 significantly differentially expressed genes which were also putative targets of several dysregulated miRNAs. RT-qPCR results indicated that the bioinformatic approach in our study was acceptable. Our data suggested that some of the genes including PKM2, STRAP and FLT3, may participate in the pathology of lung adenocarcinoma metastasis and could be applied as potential markers or therapeutic targets for lung adenocarcinoma.

Background: Acquired resistance has become the bottleneck affecting the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Studies have shown that the antidiabetic drug metformin could effectively increase the sensitivity of TKI-resistant lung cancer cells to EGFR-TKI. This study aimed to evaluate the effect of metformin in combination with EGFR-TKI on the prognosis of non-small cell lung cancer (NSCLC) patients with diabetes mellitus type 2 (DM2)., Methods: Data of NSCLC patients with DM2 who received treatment in six hospitals in China between January 2006 and January 2014 were reviewed retrospectively. They were divided into two groups: Group A, where the patients (n = 44) received EGFR-TKI plus metformin; and Group B, where the patients (n = 46) received EGFR-TKI plus hypoglycemic agents other than metformin. Prognostic differences between the two groups were assessed., Results: The median progression-free survival (PFS) and median overall survival (OS) in Group A were significantly longer than those in Group B (19.0 months vs. 8.0 months, P = .005; 32.0 months vs. 23.0 months, P = .002). The objective response rate (ORR) and disease control rate (DCR) in Group A were significantly higher than those in Group B (70.5% vs. 45.7%, P = .017; 97.7% vs. 80.4%, P = .009). Secondary data analysis showed that metformin use significantly prolonged the median PFS in subgroups using either first-line EGFR-TKI or second-line EGFR-TKI., Conclusions: Metformin and EGFR-TKI have a synergistic effect in the treatment of DM2 NSCLC patients harboring EGFR-activating mutations. Metformin use is associated with improved survival and delayed onset of acquired resistance to EGFR-TKI., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)