A molecular signature for MET-targeted therapy
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PROVIDER: PRJNA271603 | ENA |
REPOSITORIES: ENA
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Project description:Constitutive MET signaling promotes invasiveness in primary and recurrent GBM; however, current MET-targeting strategies lack of effective biomarkers for selecting suitable patients for treatment. Here, we identified a predictive signature potentially valuable for indicating vulnerability to MET-targeted therapy in GBM. The use of both human and mouse gene expression microarrays showed that MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall they impede tumor growth by inhibiting cell cycle progression. Notably, GBM tumors with EGFRamp that showed resistance to erlotinib treatment also showed activation of the MET pathway, suggesting that a combination of EGFR and MET inhibitors may overcome or prevent such resistance in patients with EGFRamp GBM.
2016-01-05 | GSE64667 | GEO
Project description:Constitutive MET signaling promotes invasiveness in primary and recurrent GBM; however, current MET-targeting strategies lack of effective biomarkers for selecting suitable patients for treatment. Here, we identified a predictive signature potentially valuable for indicating vulnerability to MET-targeted therapy in GBM. The use of both human and mouse gene expression microarrays showed that MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall they impede tumor growth by inhibiting cell cycle progression. Notably, GBM tumors with EGFRamp that showed resistance to erlotinib treatment also showed activation of the MET pathway, suggesting that a combination of EGFR and MET inhibitors may overcome or prevent such resistance in patients with EGFRamp GBM. GBM cell lines (DBM2, U251M2, U87M2, U118, and SF295) were treated for 7 days with either vehicle (n=14) or V-4084 (n=14) (i.e. SF295 + vehicle (n=2), SF295 + V-4084 (n=2), U118 + vehicle (n=3), U118 + V-4084 (n=3), U87M2 + vehicle (n=3), U87M2 + V-4084 (n=3), DBM2 + vehicle (n=3), DBM2 + V-4084 (n=3), U251M2 + vehicle (n=3), U251M2 + V-4084 (n=3)). GBM cell lines (DBM2, U251M2, U87M2, U118, and SF295) were subcutaneously inoculated into the flank region of nude mice to initiate tumor growth. Subsequently mice were treated for 7 days with either vehicle (n=14) or V-4084 (n=14) (i.e. SF295 + vehicle (n=2), SF295 + V-4084 (n=3), U118 + vehicle (n=3), U118 + V-4084 (n=3), U87M2 + vehicle (n=3), U87M2 + V-4084 (n=3), DBM2 + vehicle (n=3), DBM2 + V-4084 (n=3), U251M2 + vehicle (n=3), U251M2 + V-4084 (n=2)).
2016-01-05 | E-GEOD-64667 | biostudies-arrayexpress
Project description:This study investigates the mechanisms of resistance to MET-targeted therapy in MET-amplified lung cancer. Researchers established a lung cancer cell line resistant to MET tyrosine kinase inhibitors (MET-TKI) and found that Aurora kinase B (AURKB) inhibitors significantly inhibited the proliferation of these resistant cells. AURKB knockdown enhanced MET-TKI sensitivity, though the phosphorylation of Histone H3, an AURKB target, remained unchanged. Gene expression analysis revealed an enrichment of STAT3-activated genes, and AURKB influenced the phosphorylation of STAT3. The study also identified an elevated expression of the anti-apoptotic gene BCL2, and AURKB inhibition induced apoptosis by reducing the STAT3/BCL2 axis. The effects of AURKB inhibitors led to G2/M cell cycle arrest and apoptosis in resistant cells. AURKB overexpression was observed in post-treatment tumors from advanced MET-amplified lung cancer patients with MET-TKI resistance. This suggests that targeting AURKB may be a potential therapeutic strategy to overcome resistance to MET-TKIs in MET-amplified lung cancer.
2026-06-30 | GSE285996 | GEO
Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.
2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE27389: Substitutions in the KRas oncogene determine protein behavior: Implications for signaling and clinical outcome. GSE31428: Final efficacy and biomarker analysis of the sorafenib arm of the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) trial GSE31852: An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET. GSE33072: An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to erlotinib and PI3K pathway inhibitors and identifies Axl as a novel EMT marker in non-small cell lung cancer. Refer to individual Series
2012-01-01 | E-GEOD-31437 | biostudies-arrayexpress
Project description:To identify HGF/Met regulated genes, we performed expression microarray analysis after inducible activation of Met receptor in primary cultures of hepatocytes established from wild-type control (Alb-Cre +/-) and Met conditional knockout mice (Alb-Cre +/-; Met Fl/Fl). Keywords: time series design
2006-10-02 | GSE4451 | GEO
Project description:Targeting the MET oncoprotein is an effective strategy in precision cancer therapy, whereas its clinical efficacy varies dramatically across tumor types. To address this challenge, we explored an alternative approach to downregulate MET expression at transcriptional levels. We identified a cis-regulatory element in the MET proximal promoter region that folds into a stable parallel DNA G-quadruplex (MET-G4). We further determined the high-resolution NMR solution structure of MET-G4 and demonstrated that MET-G4 recruits the cellular LRPPRC protein to promote MET transcription, thereby uncovering a previously unrecognized epigenetic mechanism that drives MET overexpression. Moreover, we characterized the specific G4-binding domain of LRPPRC and elucidated its structural basis for recognition of the MET-G4. Through screening an in-house natural product library, we identified nitidine alkaloid (NIT) as a potent MET-G4 stabilizer. Strikingly, nitidine acts as a molecular glue, strengthening the LRPPRC-MET-G4 interaction and inducing the formation of a stable LRPPRC-NIT-MET-G4 ternary complex. This complex likely alters the structure and function of LRPPRC, ultimately leading to MET downregulation and potent anticancer effects. Notably, this is the first report of a molecular glue that stabilizes a G4-protein complex to silence an oncogene. Additionally, comprehensive in vitro and in vivo experiments demonstrated that nitidine significantly inhibits tumor progression mainly through an LRPPRC-MET-G4-dependent mechanism. Collectively, our study reveals a novel epigenetic regulatory mechanism involving LRPPRC-MET-G4-mediated MET upregulation and suggests a promising therapeutic strategy for MET-driven tumors with molecular glues that target the LRPPRC-MET-G4 interface
2026-05-19 | GSE330177 | GEO
Project description:Overcoming MET-targeted drug resistance in MET-amplified lung cancer by Aurora Kinase B inhibition
| PRJNA1207446 | ENA
Project description:Phage therapy targeted E.coli Raw sequence reads
| PRJNA1158932 | ENA
Project description:Oncogenic gene fusions have been identified in many cancers and many serve as biomarkers or targets for therapy. Here we identify six different melanocytic tumors with genomic rearrangements of MET fusing the kinase domain of MET in-frame to six different N-terminal partners. These tumors lack activating mutations in other established melanoma oncogenes. We functionally characterize two of the identified fusion proteins (TRIM4-MET and ZKSCAN1-MET) and find that they constitutively activate the mitogen-activated protein kinase (MAPK), phosphoinositol-3 kinase (PI3K), and phospholipase C gamma 1 (PLCγ1) pathways. The MET inhibitors cabozantinib (FDA-approved for progressive medullary thyroid cancer) and PF-04217903 block their activity at nanomolar concentrations. MET fusion kinases thus provide a potential therapeutic target for a rare subset of melanoma for which currently no targeted therapeutic options currently exist.
2015-12-01 | GSE67841 | GEO