Mechanisms of Acquired Resistance Following Dual EGFR/MET Inhibition in <i>MET</i> -Amplified EGFR TKI–Resistant Lung Cancer

Mesenchymal-epithelial transition factor (MET) amplification is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mechanism that 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 resistance mechanisms after dual 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 resistance mechanisms were evaluated through signal pathway analysis and next-generation sequencing. Of 12 patients with resistance after EGFR/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. Novel acquired general transcription factor IIi-BRAF fusions emerged in PE5867. Osimertinib plus trametinib reversed resistance. PE5345 os/cp R overexpressed EGFR, which was inhibited by afatinib. Additionally, amivantamab induced significant antibody-dependent cell-mediated cytotoxicity (ADCC) against PE5345, PE5867, and PE5345 os/cp R. We found that resistance after dual inhibition is 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/MET inhibition. Understanding resistance mechanisms may provide clues for subsequent therapy.