KRAS inhibitor-resistance in MET-amplified KRASG12C 1 non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanism
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ABSTRACT:
PROVIDER: PRJNA742707 | ENA |
REPOSITORIES: ENA
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Project description:Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.
2021-08-01 | GSE179212 | GEO
Project description:Background Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. Methods In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified versus non-amplified tumors by mass spectrometry. Results We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. Conclusions Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.
2025-05-07 | PXD059513 | Pride
Project description:Purpose: MET is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). To understand the mechanisms of resistance to MET-TKIs and establish therapeutic strategies, we developed an in vitro model using capmatinib-resistant cell lines (EBC-CR1, CR2, and CR3) derived from the MET-amplified NSCLC cell line EBC-1. Methods: We established capmatinib-resistant NSCLC cell lines from the MET-amplified NSCLC cell line EBC-1 and identified alternative signaling pathways using 3’mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative PCR and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the EBC-CR1, -CR2, and -CR3 resistant cell lines. Results: We found that epidermal growth factor (EGFR) mRNA expression and protein activation were increased in EBC-CR1–3 cells compared to EBC-1 cells. EBC-CR1 cells showed EGFR-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells, which overexpressed the EGFR-MET heterodimer, responded dramatically to the combination of capmatinib and the phosphoinositide-3 kinase catalytic subunit α (PIK3CA) inhibitor afatinib. In addition, EBC-CR3 cells, which had activated EGFR along with amplified PIK3CA, were sensitive to the combination of afatinib and the PI3Kα inhibitor. Conclusions: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be an effective therapeutic strategy in MET-TKI-resistant NSCLC patients.
2017-05-01 | GSE94405 | GEO
Project description:MET amplification is present in 20% of gastric cancers and has been confirmed as a therapeutic target in clinical trials. The molecular mechanisms of response and resistance to MET inhibitors are not well understood. We investigated the determinants of MET dependency in human gastric cancer. MET inhibition inhibited proliferation and induced cell death only in MET-amplified gastric cancer cell lines. The effects on growth arrest were stronger than the effects on cell death. To identify possible resistance mechanisms, we performed whole-genome mRNA expression profiling. Molecular changes related to autophagy were among the top alterations observed. Consistent with these findings, autophagy levels increased in a concentration-dependent manner when MET-amplified cells were exposed to crizotinib. Autophagy inhibition caused a dramatic decrease in apoptosis in one of the MET-amplified cell lines (MKN45) but not in the other (SNU-5). Because autophagy may provide energy in cells subjected to growth factor deprivation, we explored the effects of MET or autophagy inhibition on cellular ATP levels. This revealed that autophagy-dependent ATP production was selectively required for apoptosis in the MKN45 cells and that chemical ATP depletion mimicked the effects of autophagy inhibition to block cell death. Overall, the data reveal a novel relationship between ATP depletion and resistance to MET inhibitor-induced cell death. Our observations suggest that autophagy inhibitors could have unintended consequences when they are combined with growth factor receptor inhibitors in tumors that require autophagy-dependent ATP production for apoptosis. 12 samples triplicate samples of SNU-5 and MKN45 +/- criztonib for 24 hours
2016-05-13 | E-GEOD-77320 | biostudies-arrayexpress
Project description:Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met hepatocyte growth factor RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We observed that Met signaling converges on HER3 tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. In order to identify genes required for cancer cell proliferation in the MET-amplified setting whose expression, we stably transduced KatoII MET-amplified cells with shRNA targeting ERBB3, the gene encoding HER3. Stably-transduced cells were selected with puromycin, assayed for proliferative phenotype, and lysed for RNA extraction. Pooled libraries of total RNA were then sequenced using the Illumina HiSeq4000 platform, and differentially-expressed genes were identified from read counts normalized across samples. Differentially-expressed genes were further assayed for dependence on HER3 in other MET-amplified cell lines to identify genes recurrently dependent on HER3 in the MET-amplified setting.
2021-11-23 | GSE189461 | GEO
Project description:This phase II trial studies how well savolitinib works in treating patients with MET amplified colorectal cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Savolitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
| 2278111 | ecrin-mdr-crc
Project description:Therapeutic resistance to single-agent targeted therapies (e.g., KRASG12C inhibitors) frequently arises in tumors through adaptive mechanisms such as cellular plasticity and genetic instability. Here, we demonstrated that KRASG12C inhibitors induce BRAF membrane localization, leading to MAPK pathway reactivation in KRASG12C-mutant cancers. The engineered tethering of BRAF to the membrane significantly diminished the antitumour efficacy of the KRASG12C inhibitors. Mechanistically, ZDHHC5-mediated palmitoylation at residues Cys194/195, located within the RAS-binding domain (RBD) of BRAF, governs BRAF membrane recruitment and protein stability. Notably, BRAF palmitoylation sustains oncogenic signalling across diverse cancer types, especially in cholangiocarcinoma, and high ZDHHC5 expression is correlated with aggressive clinical behavior in KRASG12C-mutant and other MAPK-driven malignancies. Depletion of ZDHHC5 or disruption of BRAF palmitoylation at these critical sites suppressed MAPK signalling, restored sensitivity to KRASG12C inhibition, and impaired tumor progression in vitro and in vivo. Our findings identify BRAF palmitoylation as a dual regulator of therapeutic resistance and tumor progression, highlighting ZDHHC5 as a therapeutic target to overcome KRASG12C inhibitor resistance and treat BRAF palmitoylation-dependent cancers.
2025-06-02 | GSE298455 | GEO
Project description:Tumor onset and progression require the accumulation of many genetic and epigenetic lesions. Yet, there are cases in which cancer cells rely on only one of these lesions to maintain their malignant properties, and this dependency results in tumor regression upon oncogene inactivation (‘oncogene addiction’). Determining which nodes of the many networks operative in the transformed phenotype specifically mediate this drastic response to oncogene neutralization is crucial to identify the vulnerabilities of cancer. We combined multiplex phosphoproteomics, genome-wide expression profiling, and functional assays in a variety of cancer cells addicted to tyrosine kinase receptor oncogenes, using the Met receptor as the major model system. Unexpectedly, we found that Met blockade impacts on a limited subset of Met downstream signals: little or no effect was observed for many relevant pathways controlling Met-driven neoplastic growth – such as STATs, NF-kB, JNK, and p38 MAPK – and only a restricted and pathway-specific signature of Ras/PI3K transducers and transcriptional effectors was fully neutralized. An analogous signature was also generated by EGF receptor inhibition in a different cellular context, suggesting a stereotyped response that likely does not depend on receptor type or tissue origin. Biologically, cell-cycle arrest induced by Met de-activation was recapitulated by extinction of Ras/PI3K-dependent signals and was rescued by active forms of the same signals. These findings uncover ‘dominant’ and ‘recessive’ nodes among the numerous oncogenic networks regulated by tyrosine kinase receptors and active in cancer, with the Ras/PI3K pathways being the necessary and sufficient determinants of therapeutic response.
2010-03-01 | GSE19043 | GEO
Project description:cMET is a well known oncogene whose activation is widely implicated in tumorigenesis and metastasis. To investigate the effects of acute inhibitoin of cMET signaling in the mammary tumors, we inhibited cMET activation in xenograft mammary tumors that were derived from a MET amplified mouse mammary tumor cell line and analyzed the transcriptional alteration between vehicle and MET inhibitor treated tumors.
2020-02-23 | GSE52097 | GEO
Project description:Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.
2024-06-27 | GSE270541 | GEO