Synergistic antitumor effects of combination therapy with MET TKI vabametkib and a third-generation EGFR TKI lazertinib in MET-amplified EGFR-mutant NSCLC

ABSTRACT: Third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) improved outcomes in EGFR-mutant non-small cell lung cancer (NSCLC); however, the subsequent development of resistance emphasizes the necessity of overcoming this therapeutic limitation. MET amplification is one of the major resistance mechanism in EGFR-mutant NSCLC, bypassing EGFR inhibition by activating cell survival, proliferation, and metastasis. Combinining MET- and EGFR-TKIs is thus emerging as a promising therapeutic strategy to overcome resistance to EGFR TKIs. This study aimed to investigate the combination of the selective MET TKI vabametkib and a third-generation EGFR TKI lazertinib in MET amplified EGFR TKI resistance models. Signal inhibition and cytotoxicity of vabametkib plus lazertinib were evaluated in osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010) by western blot and Cell Titer-Glo assay. The in vivo efficacy was evaluated using two patient-derived xenograft (PDX) models (YHIM-1035(1) and YHIM-1053), characterized for MET amplification by whole-exome sequencing or droplet digital polymerase chain reaction (ddPCR). In vitro studies demonstrated that vabametkib plus lazertinib potently inhibited EGFR/MET phosphorylation at the nanomolar level, leading to the suppression of PI3K/AKT and MAPK signaling pathways and subsequent down-regulation. Consistently, in vivo studies revealed that vabametkib plus lazertinib significantly suppressed the growth of MET-dependent xenograft tumors, while in certain models, monotherapy also exhibited strong antitumor effects. These findings suggest that the combination of the MET TKI vabametkib and the third-generation EGFR TKI lazertinib represent a promising therapeutic strategy to overcome acquired EGFR TKI resistance in patients with MET-amplified NSCLC, potentially guiding future clinical applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307503 | GEO | 2026/09/01

REPOSITORIES: GEO