LAUSR

The third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) osimertinib is approved for untreated, or previously EGFR‐TKI–treated T790M‐positive EGFR‐mutated non‐small cell lung carcinoma (NSCLC). We investigated the heterogeneity of responses to osimertinib and its underlying mechanisms. A patient with EGFR‐L858R–mutated NSCLC was treated with erlotinib. Following treatment, he developed brain and multiple bone metastases and was eventually diagnosed with NSCLC with EGFR‐T790M mutation. The responses of various tumor specimens to osimertinib were heterogeneous. We investigated EGFR‐T790M and MET amplification using PCR and FISH in autopsy specimens of the cervical spine, lumbar spine, and brain. We established the KNZ osimertinib‐resistant (KNZ_OR) tumor cell line with MET amplification using a cervical spine lesion that was intrinsically resistant to osimertinib. We evaluated the effects of MET knockdown and MET inhibitor on KNZ_OR cell sensitivity to osimertinib in vitro and in vivo. Osimertinib‐resistant lesions (cervical spine and brain) showed EGFR‐L858R and MET amplification, but not EGFR‐T790M, whereas osimertinib‐sensitive lesions (lumbar spine) showed EGFR‐L858R and ‐T790, but not MET amplification. Osimertinib decreased the association of amplified MET with L858R‐mutated EGFR but increased that with human epidermal growth factor receptor 3 in KNZ_OR cells. MET knockdown or MET inhibitor sensitized KNZ_OR cells to osimertinib in vitro, indicating that MET amplification induced osimertinib resistance. Combination with osimertinib plus crizotinib induced tumor shrinkage in the KNZ_OR xenograft model. Hence, MET amplification might induce heterogeneous responses to osimertinib in EGFR‐mutated NSCLC. Further investigations on mutated EGFR and amplified MET might lead to the development of effective therapies.