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Long non-coding RNAs (lncRNAs) are fundamental agents that govern tumor growth and metastasis across a spectrum of cancer types. Linc01503 is a novel lncRNA situated on human chromosome 19, and it is intricately linked with the pathogenesis of multiple human cancers, underscoring its substantial role and significance in cancer development. It has been recognized as a pivotal contributor to inducing malignant behaviors in lung cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, liver cancer and pancreatic cancer, among others. The dysregulation of linc01503 has been shown to strongly associate with advanced clinicopathological factors and foretell an unfavorable prognosis, indicating its prospective clinical significance as a valuable biomarker and therapeutic target for individuals with cancer. The primary objective of the current work is to present the intricate molecular pathways governed by linc01503 and its profound clinical relevance in the context of carcinogenesis. We also focus on the future prospects of linc01503-based clinical application. This will help us to better understand the regulatory mechanism of carcinogenesis and provide new ideas for precision molecular medicine. [ABSTRACT FROM AUTHOR]

MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: EGFR mutations in non-small cell lung cancer (NSCLC) are associated with a poor response to immune checkpoint inhibitors (ICIs), and only 20% of NSCLC patients harboring EGFR mutations benefit from immunotherapy. Novel biomarkers or therapeutics are needed to predict NSCLC prognosis and enhance the efficacy of ICIs in NSCLC patients harboring EGFR mutations, especially lung adenocarcinoma (LUAD) patients, who account for approximately 40–50% of all NSCLC cases. Methods: An ARID1A-knockdown (ARID1A-KD) EGFR-mutant LUAD cell line was constructed using lentivirus. RNA-seq and mass spectrometry were performed. Western blotting and IHC were used for protein expression evaluation. Effects of 3-MA and rapamycin on cells were explored. Immunofluorescence assays were used for immune cell infiltration examination. Results: ARID1A expression was negatively associated with immune cell infiltration and immune scores for ICIs in LUAD with EGFR mutations. In vitro experiments suggested that ARID1A-KD activates the EGFR/PI3K/Akt/mTOR pathway and inhibits autophagy, which attenuates the inhibition of Rig-I-like receptor pathway activity and type I interferon production in EGFR-mutant LUAD cells. In addition, 3-MA upregulated production of type I interferon in EGFR-mutant LUAD cells, with an similar effect to ARID1A-KD. On the other hand, rapamycin attenuated the enhanced production of type I interferon in ARID1A-KD EGFR-mutant LUAD cells. ARID1A function appears to influence the tumor immune microenvironment and response to ICIs. Conclusion: ARID1A deficiency reverses response to ICIs in EGFR-mutant LUAD by enhancing autophagy-inhibited type I interferon production. 4p38v18Tik7_Gskdth_Seh Video Abstract [ABSTRACT FROM AUTHOR]

Metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the liver is the most common site of metastasis. Tumor cell metastasis can be thought of as an invasion-metastasis cascade and metastatic organotropism is thought to be a process that relies on the intrinsic properties of tumor cells and their interactions with molecules and cells in the microenvironment. Many studies have provided new insights into the molecular mechanism and contributing factors involved in CRC liver metastasis for a better understanding of the organ-specific metastasis process. The purpose of this review is to summarize the theories that explain CRC liver metastasis at multiple molecular dimensions (including genetic and non-genetic factors), as well as the main factors that cause CRC liver metastasis. Many findings suggest that metastasis may occur earlier than expected and with specific organ-anchoring property. The emergence of potential metastatic clones, the timing of dissemination, and the distinct routes of metastasis have been explained by genomic studies. The main force of CRC liver metastasis is also thought to be epigenetic alterations and dynamic phenotypic traits. Furthermore, we review key extrinsic factors that influence CRC cell metastasis and liver tropisms, such as pre-niches, tumor stromal cells, adhesion molecules, and immune/inflammatory responses in the tumor microenvironment. In addition, biomarkers associated with early diagnosis, prognosis, and recurrence of liver metastasis from CRC are summarized to enlighten potential clinical practice, including some markers that can be used as therapeutic targets to provide new perspectives for the treatment strategies of CRC liver metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Objective.: Previous studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in cervical cancer progression. Tissue inhibitor of metalloproteinases-3 (TIMP-3) can inhibit all of MMPs, and its overexpression can retard many kinds of tumor growth. Especially, a potent bystander effect would make it to be more advisable for treating cervical cancer whose primary growth pattern is to invade adjacent structures. These characters prompted the authors to explore its further applicability in human cervical cancer. Methods.: We constructed a replication deficient adenoviral vector carrying TIMP-3 (Ad-TIMP-3). It was transferred into different cervical cancer cell lines in vitro and was injected into the tumor xenografts of nude mice in vivo. Results.: Overexpression of TIMP-3 by adenovirus vector arrested cervical cancer cells in G2/M phase. It also promoted growth inhibition of cancer cells by bystander effects. Ad-TIMP-3 infection produced a more potent cell killing effect than Ad-p53 (P <0.05). A synergic effect was observed when Ad-TIMP-3 and cisplatin (cDDP) were used in combination (D <1). In vivo, Ad-TIMP-3 could inhibit cervical cancer xenografts growth. Compared with Ad-TIMP-3 and cDDP groups, tumor growth in Ad-TIMP-3 combined with cDDP group was inhibited more significantly (P <0.05). Conclusion.: These findings indicated that Ad-TIMP-3 bear a therapeutic potential for cervical cancer. [Copyright &y& Elsevier]

Abstract: Purpose/Objective. : To investigate whether exogenous PUMA expression suppresses the growth of drug-resistant choriocarcinoma cells and sensitizes them to chemotherapeutic agents. Methods. : An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents( 5-FU, vp16, MTX), was used to treat drug-resistant choriocarcinoma cells jeg-3/vp16 and parental jeg-3. The growth inhibitory and proapoptotic effects of Ad-PUMA both in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated by an analysis of caspase 3 activation and the change of mitochondrial membrane potential. The levels of PUMA, p53 and caspase 3 were detected by Western blotting. Result. : PUMA was expressed lower in jeg-3/vp16 than in jeg-3. jeg-3/vp16 responded much less sensitively to 5-FU and vp16 treatment than jeg-3, though PUMA was up-regulated in both cells. Exogenous PUMA expression resulted in potent growth suppression of jeg-3/vp16 and jeg-3 through induction of apoptosis. Ad-PUMA sensitized jeg-3 and jeg-3/vp16 to chemotherapeutic agents. When Ad-PUMA 10MOI and 5-FU, vp16 or MTX were combined respectively, IC50 of drugs decreased by 8.66-, 18.66- and 13.06-fold compared with those treated by anticancer drugs alone in jeg-3/vp16, while in jeg-3, IC50 decreased only by 1.80-, 1.78- and 2.76-fold. Ad-PUMA restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents by enhancing apoptosis induced by anticancer drugs. Similar results could be observed in vivo. Xenograft tumors were inhibited by Ad-PUMA or vp16. In the drug-resistant group, the inhibitory rate increased from 14.57% to 78.93% in vp16 and vp16 combined with Ad-PUMA subgroups. While in the parental group, the inhibitory rate increased but slightly, from 66.39% to 71.56%. Conclusion. : PUMA is an important player in the therapeutic responses to chemotherapeutic agents of choriocarcinoma cells. In addition to its role in inhibiting tumor growth, low dose of Ad-PUMA significantly restored the sensitivity of choriocarcinoma cells to chemotherapeutic agents in vitro and in vivo. Exogenous PUMA is potentially useful as a sensitizer in treating drug-resistant choriocarcinoma. [Copyright &y& Elsevier]

Abstract: Objectives: Arsenic trioxide (As2O3) was found to induce apoptosis in certain types of cancer cells including acute promyelocytic leukemia, and recently in solid tumors. We have previously demonstrated that As2O3 has a therapeutic effect on cervical cancer by apoptosis promotion in vitro and in vivo. Here we further our study on the role of arsenic trioxide in regulating invasive activity of cervical cancer cells in vitro and in vivo. Methods: The effects of As2O3 on human cervical cancer cell lines (HeLa, SiHa, Caski) adhesion, migration and invasion were observed by means of cell adhesion test, cell migration test and cell invasion test. The effects of As2O3 on p-IκB, MMP-2, E-cadherin, caveolin-1 and β-catenin protein expressions of tumor cells were determined by Western blot. In addition, the effects of As2O3 on NF-κB activity of tumor cells were analyzed by immunoblot in whole lysates, cytosol and nucleus, respectively. In animal experiments, cervical cancer cells TC-1 were injected into tail veins of C57BL/6 mice and then the mice were treated by intraperitoneal injection of different doses As2O3. Lung weights and the foci on the surface of lungs were measured. Results: As2O3 inhibited attachment of tumor cells to Fibronectin and Matrigel, reduced cell motility and inhibited tumor invasion potential. As2O3 treatment also resulted in a positive regulation of caveolin-1, upregulation of E-cadherin and decreased activity of β-catenin, NF-κB and NF-κB-regulated gene MMP-2. In animal experiments, lung weights in PBS group (0.31±0.07 g) were significantly elevated compared with those in As2O3-treated groups (0.21±0.03 g and 0.17±0.03 g) also As2O3 reduced number of metastatic lesions of lungs (15.4±3.5 vs. 8.3±2.0 and 6.3±2.3) in a dose-dependent manner. Conclusions: This study is the first to report the effectiveness of As2O3 as an inhibitor of cervical cancer invasion both in vitro and in vivo, suggesting a potential clinical application of As2O3 in cervical cancer therapies combining apoptosis induction and metastasis inhibition. [Copyright &y& Elsevier]

DNA vaccination has become an attractive immunization strategy against cancer. However, a major problem of DNA vaccination is its limited potency to be taken up by the antigen-presenting cells. In contrast, loss of immunogenic epitopes of tumour cells has urged the development of vaccines against multiple epitopes. In this study, we developed a novel strategy for the APC to efficiently cross-present a fusion tumour antigen, which contains both MHC class I-restricted and class II-restricted T-cell epitopes from Her-2/neu and p53 in a cognate manner. The N-terminus of the fusion Her-2/neu, p53 protein was linked to the sequence encoding for human secondary lymphoid-tissue chemokine for secretion and chemokinesis, and the C-terminus of the fusion protein was linked to a cell-binding domain of IgG (Fc portion, the cell-binding domain of IgG) for receptor-mediated internalization. Here, we show that the introduction of fused-gene DNA vaccine by gene gun reduced the size of established tumours and prolonged the lifespan of tumour-bearing mice. Results show that this DNA vaccination strategy can broadly enhance the antigen-specific cellular and humoral immune responses. This vaccine is capable of inducing adaptive immunity and may provide a novel, generic design for the development of therapeutic and preventive DNA vaccines. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a malignancy that poses a significant threat to women's health. The enormous disease burden has forced a wide range of researchers to develop more accurate prognostic models. Copy number alterations, which are amplifications or deletions of DNA fragments, often predict a poor prognosis. Instead, copy number alteration burden, i.e., the level of CNA, may have a good predictive value for disease prognosis. In this study, we developed a prognostic model for early breast cancer based on CNAB and simplified it. It performed excellently in two external validation sets. The increasing burden of breast cancer has prompted a wide range of researchers to search for new prognostic markers. Considering that tumor mutation burden (TMB) is low and copy number alteration burden (CNAB) is high in breast cancer, we built a CNAB-based model using a public database and validated it with a Chinese population. We collected formalin-fixed, paraffin-embedded (FFPE) tissue samples from 31 breast cancer patients who were treated between 2010 and 2014 at the National Cancer Center (CICAMS). METABRIC and TCGA data were downloaded via cBioPortal. In total, 2295 patients with early-stage breast cancer were enrolled in the study, including 1427 in the METABRIC cohort, 837 in the TCGA cohort, and 31 in the CICAMS cohort. Based on the ROC curve, we consider 2.2 CNA/MBp as the threshold for the CNAB-high and CNAB-low groupings. In both the TCGA cohort and the CICAMS cohort, CNAB-high had a worse prognosis than CNAB-low. We further simplified this model by establishing a prognostic nomogram for early breast cancer patients by 11 core genes, and this nomogram was highly effective in both the TCGA cohort and the CICAMS cohort. We hope that this model will subsequently help clinicians with prognostic assessments. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical and pathological features of endometrial cancer (EC) following breast cancer and to assess the effect of the breast cancer hormone receptor status on subsequent EC. Materials: A retrospective study based on SEER data of EC patients with a history of breast cancer. Results: A total of 2142 cases met the inclusion criteria. Compared to that of the general population, the incidence of EC following estrogen receptor-positive (ER+) breast cancer and hormone receptor-negative (HR−) breast cancer increased by approximately 16-fold and 15-fold, respectively. Histologically, the proportions of type II EC following ER+ breast cancer, HR− breast cancer and primary EC were 39.6%, 39.4% and 31.2%, respectively (P < 0.001). The proportions of G3 ECs were 26.9%, 28.2% and 19.8%, respectively (P < 0.001). The proportion of patients who died from miscellaneous malignant tumors among EC patients following breast cancer was significantly higher than the proportion of patients among primary ECs. The overall survival rate was worse for EC patients with a history of breast cancer (P < 0.001). There were no significant differences between patients with EC following ER+ breast cancer and those with EC following HR− breast cancer with regard to stage, lymphatic metastasis, outcome or cause of death. Conclusions: Compared to the general population, the incidence of EC in patients with breast cancer was increased markedly. Patients with EC following ER+ or HR− breast cancer shared the same clinicopathological features and prognoses. All patients need close monitoring regardless of breast cancer hormone receptor status. [ABSTRACT FROM AUTHOR]

We previously identified a cell cycle-dependent periodic subcellular distribution of cancer metastasis-associated antigen 1 (MTA1) and unraveled a novel role of MTA1 in inhibiting spindle damage-induced spindle assembly checkpoint (SAC) activation in cancer cells. However, the more detailed subcellular localization of MTA1 in mitotic cells and its copartner in SAC regulation in cancer cells are still poorly understood. Here, through immunofluorescent colocalization analysis of MTA1 and alpha-tubulin in mitotic cancer cells, we reveal that MTA1 is dynamically localized to the spindle apparatus throughout the entire mitotic process. We also demonstrated a reversible upregulation of MTA1 expression upon spindle damage-induced SAC activation, and time-lapse imaging assays indicated that MTA1 silencing delayed the mitotic metaphase-anaphase transition in cancer cells. Further investigation revealed that MTA1 interacts and colocalizes with Translocated Promoter Region (TPR) on spindle microtubules in mitotic cells, and this interaction is attenuated on SAC activation. TPR is well-implicated in SAC regulation via binding the MAD1-MAD2 complex, however, no interactions between MTA1 and MAD1 or MAD2 were detected in our coimmunoprecipitation (co-IP) assays, suggesting that the MTA1-TPR may represent a distinct SAC-associated complex separate from the previously reported TPR-MAD1/MAD2 complex. Our data provide new insights into the subcellular localization and molecular function of MTA1 in SAC regulation in cancer, and indicate that intervention of the MTA1-TPR interaction may be effective to modulate SAC and hence chromosomal instability (CIN) in tumorigenesis. • MTA1 localizes to the mitotic spindle apparatus during mitosis. • MTA1 is upregulated on spindle damage-induced SAC activation. • MTA1 silencing delays the mitotic metaphase-anaphase transition. • MTA1 interacts and colocalizes with TPR on the spindle apparatus. • MTA1-TPR interaction is weakened upon SAC activation. [ABSTRACT FROM AUTHOR]

Liver metastasis is the most fatal event of colon cancer patients. Warburg effect has been long challenged by the fact of upregulated oxidative phosphorylation (OXPHOS), while its mechanism remains unclear. Here, metastasis‐associated antigen 1 (MTA1) is identified as a newly identified adenosine triphosphate (ATP) synthase modulator by interacting with ATP synthase F1 subunit alpha (ATP5A), facilitates colon cancer liver metastasis by driving mitochondrial bioenergetic metabolism reprogramming, enhancing OXPHOS; therefore, modulating ATP synthase activity and downstream mTOR pathways. High‐throughput screening of an anticancer drug shows MTA1 knockout increases the sensitivity of colon cancer to mitochondrial bioenergetic metabolism‐targeted drugs and mTOR inhibitors. Inhibiting ATP5A enhances the sensitivity of liver‐metastasized colon cancer to sirolimus in an MTA1‐dependent manner. The therapeutic effects are verified in xenograft models and clinical cases. This research identifies a new modulator of mitochondrial bioenergetic reprogramming in cancer metastasis and reveals a new mechanism on upregulating mitochondrial OXPHOS as the reversal of Warburg effect in cancer metastasis is orchestrated. [ABSTRACT FROM AUTHOR]

Background: Crizotinib was granted accelerated approval by the Food and Drug Administration in 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). To evaluate the efficacy and safety of crizotinib, we performed a meta-analysis of published clinical trials using the random effect model.Methods: The efficacy and safety of crizotinib was evaluated based on 1-year overall survival (OS), progression-free survival (PFS), overall response rate (ORR), partial response, complete response, stable disease, and dose reduction or cessation because of crizotinib toxicity.Results: Six clinical trials were included in the meta-analysis. Crizotinib treatment demonstrated a 1-year OS of 66.8% (95% CI, 52.2-78.8%) and a PFS of 8.6 months (95% CI, 7.3-9.9 months). The aggregate ORR, partial response and complete response rates were 61.2%, 59.8% and 1.5%, respectively. The proportion of patients achieving stable disease was 42.6% (95% CI, 17.3-72.5%). The most frequently reported adverse effects of crizotinib were mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, reduction in glomerular filtration rate, and generally reversible but sometimes severe elevations in aspartate aminotransferase and alanine aminotransferase. The proportion of patients who required dose reduction or cessation because of crizotinib toxicity was 6.5% (95% CI, 4.1-10.1%).Conclusions: This meta-analysis revealed extended survival and improved response rates in patients treated with crizotinib. As a novel, targeted anticancer agent, crizotinib appears to be a favorable treatment option for patients with locally advanced or metastatic ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) metastasis is the leading cause of poor prognosis and therapeutic failure. However, the mechanisms underlying cancer metastasis are far from clear. Methods: We screened candidate genes related to metastasis through genome-wide CRISPR screening and high-throughput sequencing of patients with metastatic BC, followed by a panel of metastatic model assays. The effects of tetratricopeptide repeat domain 17 (TTC17) on migration, invasion, and colony formation ability together with the responses to anticancer drugs were investigated in vitro and in vivo. The mechanism mediated by TTC17 was determined by RNA sequencing, Western blotting, immunohistochemistry, and immunofluorescence. The clinical significance of TTC17 was evaluated using BC tissue samples combined with clinicopathological data. Results: We identified the loss of TTC17 as a metastasis driver in BC, and its expression was negatively correlated with malignancy and positively correlated with patient prognosis. TTC17 loss in BC cells promoted their migration, invasion, and colony formation capacity in vitro and lung metastasis in vivo. Conversely, overexpressing TTC17 suppressed these aggressive phenotypes. Mechanistically, TTC17 knockdown in BC cells resulted in the activation of the RAP1/CDC42 pathway along with a disordered cytoskeleton in BC cells, and pharmacological blockade of CDC42 abolished the potentiation of motility and invasiveness caused by TTC17 silencing. Research on BC specimens demonstrated reduced TTC17 and increased CDC42 in metastatic tumors and lymph nodes, and low TTC17 expression was linked to more aggressive clinicopathologic characteristics. Through screening the anticancer drug library, the CDC42 inhibitor rapamycin and the microtubule-stabilizing drug paclitaxel showed stronger inhibition of TTC17-silenced BC cells, which was confirmed by more favorable efficacy in BC patients and tumor-bearing mice receiving rapamycin or paclitaxel in the TTC17Low arm. Conclusions: TTC17 loss is a novel factor promoting BC metastasis, that enhances migration and invasion by activating RAP1/CDC42 signaling and sensitizes BC to rapamycin and paclitaxel, which may improve stratified treatment strategies under the concept of molecular phenotyping-based precision therapy of BC. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulated ARID1A expression is frequently detected in lung adenocarcinoma (LUAD) and mediates significant changes in cancer behaviors and a poor prognosis. ARID1A deficiency in LUAD enhances proliferation and metastasis, which could be induced by activation of the Akt signaling pathway. However, no further exploration of the mechanisms has been performed. Methods: Lentivirus was used for the establishment of the ARID1A knockdown (ARID1A-KD) cell line. MTS and migration/invasion assays were used to examine changes in cell behaviors. RNA-seq and proteomics methods were applied. ARID1A expression in tissue samples was determined by IHC. R software was used to construct a nomogram. Results: ARID1A KD significantly promoted the cell cycle and accelerated cell division. In addition, ARID1A KD increased the phosphorylation level of a series of oncogenic proteins, such as EGFR, ErbB2 and RAF1, activated the corresponding pathways and resulted in disease progression. In addition, the bypass activation of the ErbB pathway, the activation of the VEGF pathway and the expression level changes in epithelial–mesenchymal transformation biomarkers induced by ARID1A KD contributed to the insensitivity to EGFR-TKIs. The relationship between ARID1A and the sensitivity to EGFR-TKIs was also determined using tissue samples from LUAD patients. Conclusion: Loss of ARID1A expression influences the cell cycle, accelerates cell division, and promotes metastasis. EGFR-mutant LUAD patients with low ARID1A expression had poor overall survival. In addition, low ARID1A expression was associated with a poor prognosis in EGFR-mutant LUAD patients who received first-generation EGFR-TKI treatment. 7Ri7oJWPiw-vggUB99u973 Video abstract [ABSTRACT FROM AUTHOR]

Purpose: We used targeted capture sequencing to analyze TP53‐mutated circulating tumor DNA (ctDNA) in metastatic breast cancer patients and to determine whether TP53 mutation has predictive value for anti‐human epidermal growth factor receptor 2 (HER2) treatment for in HER2 amplification‐positive patients (HER2+) and HER2 mutation‐positive, amplification‐negative (HER2−/mut) patients. Patients and Methods: TP53 mutation features were analyzed in the Geneplus cohort (n = 1184). The MSK‐BREAST cohort was used to explore the value of TP53 mutation in predicting anti‐HER‐2 antibody efficacy. Sequencing of ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2+ patients), and an investigator‐initiated phase II study of pyrotinib (HER2−/mut patients) were performed to analyze the relationships between TP53 mutation and prognosis for HER2 TKIs. The MSK‐BREAST cohort, MutHER, and SUMMIT cohort were used for verification. Results: TP53 mutations were detected in 53.1% (629/1184) of patients in the Geneplus cohort. The TP53 mutation rate was higher in HR‐negative (p < 0.001) and HER2 amplification‐positive (p = 0.015) patients. Among patients receiving anti‐HER2 antibody therapy, those whose tumors carried TP53 mutations had a shorter PFS (p = 0.004). However, the value of TP53 mutation in predicting HER2 TKI response was inconsistent. In HER2+ patients, no difference in PFS was observed among patients with different TP53 statuses in the combined analysis of the pyrotinib phase Ib, phase Ic, and phase II clinical trials (p = 1.00) or in the MSK‐BREAST cohort (p = 0.62). In HER2−/mut patients, TP53 mutation‐positive patients exhibited a trend toward worse prognosis with anti‐HER2 TKI treatment than TP53‐wild‐type patients in our investigator‐initiated phase II study (p = 0.15), and this trend was confirmed in the combined analysis of the MutHER and SUMMIT cohorts (p = 0.01). Conclusions: TP53 mutation can be used to identify biomarkers of anti‐HER2 antibody drug resistance in HER2+ patients and HER2 TKI resistance in HER2−/mut patients. [ABSTRACT FROM AUTHOR]

Summary Splicing dysregulation is one of the molecular hallmarks of cancer. However, the underlying molecular mechanisms remain poorly defined. Here we report that the splicing factor RBM4 suppresses proliferation and migration of various cancer cells by specifically controlling cancer-related splicing. Particularly, RBM4 regulates Bcl-x splicing to induce apoptosis, and coexpression of Bcl-xL partially reverses the RBM4-mediated tumor suppression. Moreover, RBM4 antagonizes an oncogenic splicing factor, SRSF1, to inhibit mTOR activation. Strikingly, RBM4 expression is decreased dramatically in cancer patients, and the RBM4 level correlates positively with improved survival. In addition to providing mechanistic insights of cancer-related splicing dysregulation, this study establishes RBM4 as a tumor suppressor with therapeutic potential and clinical values as a prognostic factor. [ABSTRACT FROM AUTHOR]

Alhtough anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumour progression. To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using the CRISPR/Cas9 knockout technique based on data mining across TCGA data sets and verified the candidate target in preclinical models and breast cancer high-throughput sequencing data sets. We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitise or resensitise HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumour tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harbouring a markedly shortened progression-free survival (PFS) (median PFS: 4.3 months versus 6.9 months; hazards ratio [HR] = 2.26 [95% confidence interval [CI] = 1.32–3.86]; P = 0.0028). Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitising or resensitising the tumours to anti-HER2 TKIs treatment. • CRISPR/Cas9 knockout library screening identified CDK12 linking anti-HER2 TKIs resistance. • CDK12 inhibition increased the efficacy of anti-HER2 tyrosine kinase inhibitors lapatinib. • CDK12 suppression repressed activation of PI3K/AKT signalling pathway. • HER2+ breast cancer patients with CDK12-amplification are resistant to HER2-targeted treatment. [ABSTRACT FROM AUTHOR]

Metastasis-associated protein 1 (MTA1) is upregulated in multiple malignancies and promotes cancer proliferation and metastasis, but whether and how MTA1 promotes esophageal squamous cell carcinoma (ESCC) tumorigenesis remain unanswered. Here, we established an ESCC model in MTA1 transgenic mice induced by the chemical carcinogen 4-nitroquinoline 1-oxide (4-NQO) and found that MTA1 promotes ESCC tumorigenesis in mice. MTA1 overexpression was observed in ESCC cells and clinical ESCC samples. Overexpressed MTA1 increased colony formation and the invasiveness and migration of ESCC cells, whereas knock down of MTA1 in ESCC cells significantly decreased colony formation, invasion and migration in vitro and inhibited the growth of xenograft tumors in vivo. RNA sequencing (RNA-seq) analysis combined with western blot assays revealed that MTA1 promotes carcinogenesis by enhancing MEK/ERK/p90RSK signaling. The phosphorylation of MEK, ERK and their downstream target p90RSK was significantly decreased after MTA1 knockdown in ESCC cells and was increased in MTA1-overexpressing cells. Moreover, colony formation, invasion and migration potential were dramatically suppressed when cells overexpressing MTA1 were treated with MEK (PD0325901) or ERK (SCH772948) inhibitors. In conclusion, MTA1 plays a pivotal oncogenic role in ESCC tumorigenesis and development through activating the MEK/ERK/p90RSK pathway. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical and pathological features of endometrial cancer (EC) following breast cancer and to assess the effect of the breast cancer hormone receptor status on subsequent EC.Materials: A retrospective study based on SEER data of EC patients with a history of breast cancer.Results: A total of 2142 cases met the inclusion criteria. Compared to that of the general population, the incidence of EC following estrogen receptor-positive (ER+) breast cancer and hormone receptor-negative (HR-) breast cancer increased by approximately 16-fold and 15-fold, respectively. Histologically, the proportions of type II EC following ER+ breast cancer, HR- breast cancer and primary EC were 39.6%, 39.4% and 31.2%, respectively (P < 0.001). The proportions of G3 ECs were 26.9%, 28.2% and 19.8%, respectively (P < 0.001). The proportion of patients who died from miscellaneous malignant tumors among EC patients following breast cancer was significantly higher than the proportion of patients among primary ECs. The overall survival rate was worse for EC patients with a history of breast cancer (P < 0.001). There were no significant differences between patients with EC following ER+ breast cancer and those with EC following HR- breast cancer with regard to stage, lymphatic metastasis, outcome or cause of death.Conclusions: Compared to the general population, the incidence of EC in patients with breast cancer was increased markedly. Patients with EC following ER+ or HR- breast cancer shared the same clinicopathological features and prognoses. All patients need close monitoring regardless of breast cancer hormone receptor status. [ABSTRACT FROM AUTHOR]

Background: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus.Methods: Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing.Results: In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9-6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05).Conclusions: Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus. [ABSTRACT FROM AUTHOR]

Deep learning-based in silico alternatives have been demonstrated to be of significant importance in the acceleration of the drug discovery process and enhancement of success rates. Cyclin-dependent kinase 12 (CDK12) is a transcription-related cyclin-dependent kinase that may act as a biomarker and therapeutic target for cancers. However, currently, there is no high selective CDK12 inhibitor in clinical development and the identification of new specific CDK12 inhibitors has become increasingly challenging due to their similarity with CDK13. In this study, we developed a virtual screening workflow that combines deep learning with virtual screening tools and can be applied rapidly to millions of molecules. We designed a Transformer architecture Drug-Target Interaction (DTI) model with dual-branched self-supervised pre-trained molecular graph models and protein sequence models. Our predictive model produced satisfactory predictions for various targets, including CDK12, with several novel hits. We screened a large compound library consisting of 4.5 million drug-like molecules and recommended a list of potential CDK12 inhibitors for further experimental testing. In kinase assay, compared to the positive CDK12 inhibitor THZ531, the compounds CICAMPA-01, 02, 03 displayed more effective inhibition of CDK12, up to three times as much as THZ531. The compounds CICAMPA-03, 05, 04, 07 showed less inhibition of CDK13 compare to THZ531. In vitro , the IC50 of CICAMPA-01, 04, 05, 06, 09 was less than 3 μM in the HER2 positive CDK12 amplification breast cancer cell line BT-474. Overall, this study provides a highly efficient and end-to-end deep learning protocol, in conjunction with molecular docking, for discovering CDK12 inhibitors in cancers. Additionally, we disclose five novel CDK12 inhibitors. These results may accelerate the discovery of novel chemical-class drugs for cancer treatment. [Display omitted] • Dual-branched pre-training deep learning framework improves drug-target interaction prediction on enzyme. • Virtual screening on 4.5 million molecules using deep learning, docking and MMGBSA scoring. • Disclose five novel and promising CDK12 inhibitors through kinase assays and in vitro tests. [ABSTRACT FROM AUTHOR]

The mechanism underlying the aggressive behaviors of triple negative breast cancer (TNBC) is not well characterized yet. The association between cancer stem cell (CSC) population and the aggressive behaviors of TNBC has not been established. We found the CD44 + /CD24 − cell population was enriched in TNBC tissues and cell lines, with a higher capacity of proliferation, migration, invasion and tumorigenicity as well as lower adhesion ability. The CD44 + /CD24 − cell population with cancer stem cell-like properties may play an important role in the aggressive behaviors of TNBC. This discovery may lead to new therapeutic strategies targeting CD44 + /CD24 − cell population in TNBC. [ABSTRACT FROM AUTHOR]