Abstract
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.