Insensitivity of oncogenic EGFR R776L mutation to EGFR inhibitors in lung cancer

Non-small cell lung cancers (NSCLC) account for 85 % of total lung cancers. Mutation in EGFRdrives the progress of NSCLSs with high mortality rate. Besides the common mutations in EGFR, which together comprise of 85 % of all EGFR mutations and respond to the targeted therapy of EGFR tyrosine kinase inhibitors (TKIs), many other low-frequency mutations of EGFR are existed in patients. The oncogenic roles and sensitivity of these mutations to EGFR TKIs are not fully understood yet. Here we described two cases of lung adenocarcinoma patients harboring EGFR R776L missense mutation, showed PD and SD after treatment with third-generation EGFR inhibitor, Almonertinib. Chemotherapy afterward showed PR effect in one patient with PSF of 10 months. We also explored the oncogenic feature of single R776L mutation by Ba/F3 isogenic cells and found that, EGFR R776L mutation activates EGFR-related survival signaling pathway in Ba/F3 cells, and they are insensitive to gefitinib, afatinib, and Almonertinib, which consistent with our clinical observation.