Novel Resistance Mechanisms to Osimertinib Analysed by Whole-Exome Sequencing in Non-Small Cell Lung Cancer

Abstract

PurposeMolecular-based targeted therapy has improved life expectancy for advanced non-small cell lung cancer (NSCLC). However, it does not have to be inevitable that patients receiving third-generation EGFR-TKIs become drug resistant. EGFR C797S and MET amplification are common mechanisms of osimertinib. However, a large part of these potential drug mechanisms remains unknown, and further research is needed.MethodsTumour and blood samples from forty advanced NSCLC patients were identified as acquired drug resistant to osimertinib. The NGS panel was applied to detect EGFR C797S and MET amplification in tumour tissues or plasma samples. Whole-exome sequencing was conducted in five pairs of tumour tissues obtained before osimertinib administration and after osimertinib resistance in patients without C797S/cMET amplification.ResultsThe overall C797S mutation rate was 20%, and MET amplification was detected in six out of sixteen C797S-negative samples. PDGFRA in the PI3K-AKT-mTOR signalling pathway, RASAL2, RIN3 and SOS2 in the RAS-Raf-ERK signalling pathway, PTK2 in the ERBB signalling pathway and ABCC1 and ABCB5 in the ABC membrane pump system were identified as candidate crucial genes of drug resistance to osimertinib.ConclusionEGFR C797S mutation and MET amplification are leading mechanisms for osimertinib resistance in lung cancer. The crucial potential mutated genes defined in our present study may need further validation in a considerable number of lung cancer patients.