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Expression profiling of MET TKI resistant Hs746T cells.

ABSTRACT: MET exon 14 skipping mutations (METΔex14) are oncogenic drivers in ~3-5% of lung cancer, which can be targeted with MET tyrosine kinase inhibitors (TKIs). The emergence of resistance limits long-term responses and is commonly mediated by secondary genomic alterations. We devised a preclinical strategy to study MET-TKI resistance using a novel dose escalation approach on METΔex14-dependent cancer cells to generate MET-TKI-refractory isogenic counterparts. Targeted sequencing of resistant clones identified acquired mutations in SPOP and MGA, both antagonists of MYC activity. Further investigation of SPOP and MGA interactomes confirmed MYC as the likeliest target shared between their regulatory networks. SPOP- and MGA-mutant clones exhibited high MYC levels and transcriptomic signatures of MYC activation. Ectopic expression of MYC rescued tumor growth in the presence of TKI, while MYC depletion mimicked the cytotoxic effect of TKI treatment, indicating that MYC activity is coupled to MET signaling and MYC is required to mediate drug resistance. Analysis of a clinical cohort of METΔex14-positive lung cancer revealed several cases where acquired MYC pathway alterations mediated resistance to MET-TKIs. These findings collectively converge on MYC as a key pathway in the progression of MET TKI-resistant cancers, and our in vitro data support the strategy of co-targeting MYC and MET to yield more prolonged responses in patients with METΔex14-positive lung cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298399 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.

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Expression profiling of MET TKI resistant Hs746T cells.

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