BACKGROUND: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have substantially improved the clinical outcomes of patients with EGFR-mutated non-small cell lung cancer (NSCLC), most patients ultimately develop acquired resistance. MET amplification is a common resistance mechanism to EGFR-TKIs; however, its effects on receptor dimerization and the resulting dependence on EGFR or MET signaling have not been fully elucidated. METHODS: We established a classical lung cancer cell line model with acquired resistance to osimertinib, a third-generation EGFR-TKI, through exposure to the drug (HCC827OR). Activation profiles of phospho-receptor tyrosine kinases and genomic alterations were investigated, and drug sensitivity to osimertinib and the MET-TKI savolitinib was evaluated. EGFR and MET signaling status and dimerization/interaction of EGFR, MET, and ERBB3 were analyzed. In addition, exogenous MET overexpression was introduced into parental HCC827 cells to assess its effects on drug sensitivity and receptor dimerization. RESULTS: HCC827OR cells exhibited MET amplification and showed sensitivity to savolitinib monotherapy. ERBB3 phosphorylation correlated with the efficacy of the TKIs. Consistently, we found reduced interaction between EGFR and ERBB3 and increased interaction between MET and ERBB3 in HCC827OR cells. MET homodimers and MET-EGFR interaction increased while EGFR homodimers decreased in those cells. Exogenous MET overexpression in the parental cells partially recapitulated the drug-resistant phenotype, showing partial sensitivity to savolitinib, increased MET homodimers, and decreased EGFR homodimers. CONCLUSIONS: MET amplification alters the balance of EGFR/MET/ERBB3 dimerization, leading to a shift in signaling dependence from EGFR to MET. These findings provide insight into therapeutic strategies for EGFR-mutated NSCLC.
Yagami et al. (Tue,) studied this question.