MET扩增的EGFR TKI耐药肺癌在双重EGFR/MET抑制后的获得性耐药机制

MET amplification is an EGFR tyrosine kinase inhibitor (TKI) resistance mechanism in lung cancer, which may be overcome by dual inhibition of EGFR and MET. However, acquired resistance after dual inhibition still occurs, and the mechanisms remain largely unknown. We analyzed resistant mechanisms after dual EGFR and MET inhibition for MET amplification-mediated EGFR TKI resistance in lung cancer. Patient-derived cell lines were established before and after acquired resistance to dual inhibition if possible. Potential resistant mechanisms were evaluated through signal pathway analysis and next-generation sequencing. Of 12 patients with resistance after dual EGFR and MET inhibition, 5 (42%) acquired oncogenic fusions (3 BRAF fusions, 1 ALK fusion and 1 RET fusion), 1 (8%) developed EGFR T790M, 1 (8%) exhibited EGFR C797S, and 1 (8%) transformed to small cell. The EGFR T790M and ALK fusion responded to subsequent targeted therapies. Serial cell lines from a patient with EGFR L858R and MET amplification (PE5345), after resistance to osimertinib and capmatinib through gradual escalation of drug exposure in vitro (PE5345 os/cp R), and after clinical resistance to osimertinib and capmatinib (PE5867), were propagated. After combined inhibition with osimertinib and capmatinib, sustained ERK signaling was observed in PE5867, whereas sustained activation of EGFR and AKT was detected in PE5345 os/cp R. Novel acquired GTF2I-BRAF fusions emerged in PE5867. Osimertinib plus trametinib reversed resistance. EGFR and HER2 amplifications were discovered in PE5345 os/cp R, which could be inhibited by afatinib. Additionally, amivantamab induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) against PE5345, PE5867, and PE5345 os/cp R. We found resistant mechanisms after dual inhibition are heterogeneous, but some might still be targetable. Amivantamab induced significant ADCC against both MET-amplified EGFR TKI-resistant cancer and resistant cells after dual EGFR and MET inhibition. Understanding resistance mechanisms may provide clues for subsequent therapy.