Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer

• Published in: British journal of cancer 2023-06, Vol.128 (12), p.2186-2196
• Main Authors: Choi, Yu-Ra, Kang, Eun Hye, Kim, Sunshin, Park, Seog‑Yun, Han, Ji-Youn, Lee, Youngjoo
• Format: Article
• Language: English
• Subjects: 631/67/1612/1350; 631/80; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell proliferation; Cloning; Copy number; Drug Resistance; Drug Resistance, Neoplasm - genetics; Epidemiology; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gefitinib; Gene frequency; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MET protein; Molecular Medicine; Mutants; Mutation; Non-small cell lung carcinoma; Oncology; Patients; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - genetics; Signal transduction; Small cell lung carcinoma; Toxicity
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-023-02264-4

Background In EGFR -mutant and MET -amplified lung cancer resistant to EGFR inhibitors, double blockade of EGFR and MET is considered as a reasonable strategy despite increasing toxicity. This study evaluated the single MET inhibition in these specific tumours. Methods We investigated the efficacy of a single MET inhibitor in EGFR -mutant, MET -amplified lung cancer cells (HCC827GR) and the matched clinical cases and patient-derived cells. Acquired resistance mechanisms to single MET inhibitor were further explored. Results Single MET inhibitor sufficiently inhibited the EGFR downstream signalling and proliferation in the HCC827GR cells. The MET-inhibitor-sensitive clones had similar EGFR mutation allele frequency as the MET-inhibitor-resistant clones. The patients with EGFR -mutant, MET -amplified lung cancer resistant to EGFR inhibitors showed definite response to single MET inhibitor but the response duration was not durable. The MET gene copy number in their plasma circulating tumour DNA was significantly decreased during the treatment and was not re-increased after progression. In the cells resistant to single MET inhibitor, the EGFR pathway was reactivated, and gefitinib alone successfully suppressed their growth. Conclusions Single MET inhibition produced a short-lived response in EGFR -mutant and MET -amplified lung cancer. A further study of a novel combination therapy schedule is needed to achieve long-lasting efficacy and less toxicity.