Reference - Detail
RRC ID | 69806 |
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Author | Katayama Y, Yamada T, Tokuda S, Okura N, Nishioka N, Morimoto K, Tanimura K, Morimoto Y, Iwasaku M, Horinaka M, Sakai T, Kita K, Yano S, Takayama K. |
Title | Heterogeneity among tumors with acquired resistance to EGFR tyrosine kinase inhibitors harboring EGFR-T790M mutation in non-small cell lung cancer cells. |
Journal | Cancer Med |
Abstract |
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. |
Volume | 11(4) |
Pages | 944-955 |
Published | 2022-2-1 |
DOI | 10.1002/cam4.4504 |
PMID | 35029047 |
PMC | PMC8855901 |
MeSH | Carcinoma, Non-Small-Cell Lung* / drug therapy Carcinoma, Non-Small-Cell Lung* / genetics Carcinoma, Non-Small-Cell Lung* / pathology Drug Resistance, Neoplasm / genetics ErbB Receptors Gefitinib / pharmacology Humans Lung Neoplasms* / drug therapy Lung Neoplasms* / genetics Lung Neoplasms* / pathology Mutation Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use |
IF | 3.491 |
Resource | |
Human and Animal Cells | PC-9(RCB4455) |