Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with EGFR-T790M mutantion non-small-cell lung cancer (NSCLC) who fail treatment with first-generation EGFR TKIs. Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is EGFR-C797S mutation. Other mechanisms, such as MET amplifications and BRAF, and PIK3CA mutations, were also reported. In this study, we performed gene mutational profiling in a cohort of 117 EGFR-T790M NSCLC patients and acquired resistance to osimertinib using targeted NGS.
A total of 117 patients with stage IIIb-IV EGFR-T790M NSCLC were undergoing tumor biopsies, blood or serous effusions withdrawing by the time of acquiring resistance to osimertinib. We used targeted NGS to detect genes status of patients.
In total, we identified 213 genetic alterations with a median of 4 mutations per patient. 58.12% (68/117) of patients still exhibit EGFR-T790M, 71.79% (84/117) of patients still exhibit EGFR sensitive mutations and 23.08% (27/117) of patients acquired EGFR-C797S mutations [Cis structure: 51.85% (14/27); Trans structure: 66.67% (18/27); Cis and trans structure coexistence: 18.52% (5/27)]. Besides other known resistance mechanisms, we identified MET amplification 16.24% (19/117) of patients, PIK3CA mutations in 10.26% (12/117) of patients, and KRAS mutations in 8.55% (10/117) of patients. Interestingly, we also observed TMPRSS2 and KIAA0226 mutations in EGFR-C797S/L718Q/L844V/L792F wild patients, which are restricted to osimertinib treatment resistance.
Our study uncovered mutational profiles of NSCLC patients with osimertinib resistance with potential therapeutic implications, and this study also is first study to depict the genetic landscapes comprehensively in Chinese NSCLC population resistant to osimertinib. Our analysis strongly suggests that MET amplification, PIK3CA mutations and KRAS mutations may serve as bypass resistance mechanisms in patients who are EGFR-C797S/L718Q/L844V/L792F wild type.
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All authors have declared no conflicts of interest.