Potential resistance mechanisms revealed by targeted sequencing from lung adenocarcinoma patients with primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

EGFR-TKIs have greatly improved the prognosis of lung adenocarcinoma. However, approximately 5%-10% lung adenocarcinoma patients with EGFR sensitive mutations have primary resistance to EGFR-TKIs treatment. The underlying mechanism is unknown.This study used next-generation sequencing (NGS) to explore the mechanisms of primary resistance by analyzing 11 patients with primary resistance and 11 patients sensitive to EGFR-TKIs. NGS targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was initially detected by amplification-refractory mutation system (ARMS).Potential primary resistance mechanisms were revealed by mutations unique to the EGFR-TKIs resistance group. Among the 11 resistant patients, 45% (5/11) harbored a known resistance mechanism, such as MET amplification de novo T790M mutation, or overlapping T790M and PTEN loss and Her2 amplification. In 6 of 11 resistant cases (54%), potential novel mutations that might lead to drug resistance were identified (including TGFBR1 mutation and/or EGFR structure rearrangement MTOR mutation; TMPRSS2 fusion gene and MYC amplification). By analyzing somatic mutation patterns, the frequency of C:G→T:A transitions in the patients with primary resistance was significantly higher than that in sensitive group and occurs more frequently in the non CpG region (Cp(A/C/T)→T).The mechanisms of EGFR-TKIs primary resistance may be highly heterogeneous. Mutations in EGFR and its downstream pathway as well as mutations that affect tumor cell function are related to primary resistance. Somatic single-nucleotide mutation patterns might associated with EGFR-TKIs primary resistance.