奥西默替尼
允许的
突变体
肺癌
癌症研究
癌症
生物
神经科学
细胞生物学
医学
腺癌
内科学
遗传学
基因
ROS1型
作者
Bomiao Hu,Marc Wiesehöfer,Fernando J. de Miguel,Zongzhi Liu,Lok-Hei Chan,Jungmin Choi,Mary Ann Melnick,Anna Arnal Estape,Zenta Walther,Dejian Zhao,Francesc López‐Giráldez,Anna Wurtz,Guoping Cai,Rong Fan,Scott Gettinger,Andrew Xiao,Qin Yan,Robert Homer,Don X. Nguyen,Katerina Politi
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-02-15
卷期号:84 (8): 1303-1319
被引量:2
标识
DOI:10.1158/0008-5472.can-23-0438
摘要
Abstract The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. Significance: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188
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