Heterogeneity among tumors with acquired resistance to EGFR tyrosine kinase inhibitors harboring EGFR‐T790M mutation in non‐small cell lung cancer cells

EGFR‐T790M mutation is a major mechanism underlying acquired resistance to first‐ and second‐generation EGFR tyrosine kinase inhibitors (EGFR‐TKIs) in lung cancer with mutated EGFR. However, differences in the biological characteristics of T790M tumors based on treatment regimens with each generation of EGFR‐TKI are not fully understood. We established cell lines with acquired resistance harboring EGFR‐T790M mutation derived from xenograft tumors treated with each generation of EGFR‐TKI and examined their biological characteristics with respect to third‐generation EGFR‐TKI osimertinib sensitivity. Second‐generation EGFR‐TKI dacomitinib‐resistant cells with T790M‐exhibited higher sensitivity to osimertinib than first‐generation EGFR‐TKI gefitinib‐resistant cells with T790M via inhibition of AKT and ERK signaling and promotion of apoptosis. Furthermore, gefitinib‐resistant cells showed enhanced intratumor heterogeneity accompanied by genomic instability and activation of alternative resistance mechanisms compared with dacomitinib‐resistant cells; this suggests that the maintenance of EGFR dependency after acquiring resistance might depend on the type of EGFR‐TKI. Our results demonstrate that the progression of tumor heterogeneity via both genetic and non‐genetic mechanisms might affect osimertinib sensitivity in tumors with acquired resistance harboring EGFR‐T790M mutation.