MET

This study investigated additional genetic alterations in MET-amplified gastric cancers (GCs), which are associated with poor prognosis and limited response to targeted therapies. Researchers found that MET amplification is frequently accompanied by co-amplifications of other oncogenes located on chromosome 7, such as BRAF, CDK6, and EGFR, in 54% of cases. These co-amplifications exhibit significant intra- and intertumoral heterogeneity. This complex heterogeneity may explain the diagnostic and therapeutic challenges, subclonal evolution, and the failure of targeted therapies in MET-amplified GCs.

This study investigates histologic transformation to lung squamous cell carcinoma (LUSC) in EGFR-mutant lung adenocarcinoma (LUAD) patients, an underrecognized resistance mechanism. Multiomic analyses revealed that patients with transforming or adenosquamous (LUAS) phenotypes experienced shorter overall survival on first-line osimertinib. Inactivation of the retinoblastoma (Rb) pathway, particularly via CDKN2A/B deletions, was identified as a key driver of this transformation. Furthermore, MET pathway upregulation was observed, and combined EGFR and MET inhibition demonstrated efficacy in preclinical models. These findings suggest novel strategies to counteract this aggressive form of resistance.

The prospective, multicenter ELIOS study characterized acquired resistance mechanisms to first-line osimertinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). By analyzing paired tumor biopsies taken pre-treatment and post-progression, the study identified frequent alterations including MET amplification, CDKN2A/CDKN2B and MTAP deletions, and the EGFR C797S mutation. Proteogenomic analysis also revealed high TROP2 expression, irrespective of genetic alterations. The findings highlight the heterogeneous nature of resistance and the complementary utility of tissue and liquid biopsies for alteration detection. This study emphasizes the need for therapeutic strategies targeting multiple resistance pathways.