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

EGFR-TKI-resistant EGFR T790M-mutant tumors were developed in vivo. A difference in sensitivity to osimertinib was observed between the T790M tumors. A difference in genetic and epigenetic intratumor heterogeneity was observed. AbstractEGFR-T790M mutation is a major mechanism underlying acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer with mutatedEGFR. 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 harboringEGFR-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 a...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: RESEARCH ARTICLE Source Type: research