Whole-exome sequencing identifies key mutated genes in T790M wildtype/cMET-unamplified lung adenocarcinoma with acquired resistance to first-generation EGFR tyrosine kinase inhibitors.

Purpose: Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma harboring EGFR-activating mutations will inevitably acquire resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance.

Methods: Tumor and blood samples from 69 stage IIIB-IV NSCLC patients defined as acquired resistance to first-generation EGFR TKIs (gefitinib, erlotinib or ecotinib) were collected. The cobas and Droplet digital PCR (ddPCR) were used to detect T790M mutations in tumor samples and plasma ctDNA. cMET amplification was evaluated by fluorescence in situ hybridization (FISH). Exome sequencing was performed in four T790M wildtype/cMET-unamplified samples.

Results: The overall T790M-positive rate was 52.2% considering all testing methods. Out of 21 samples in which tumor re-biopsy was performed, 14 were T790M positive (66.7%). cMET amplification was identified in three out of seven T790M-negative samples. Exome sequencing in four T790M wildtype/cMET-unamplified samples and paired white blood cells identified a cohort of candidate key mutated genes including BRAF, FGFR1, PAK1, PCNT, PEBP4 and SOX3.

Conclusions: EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistance in lung adenocarcinoma. These key mutated genes identified in the present study would need further validation in large number of patients.