ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.

Autor:	Hu B; Department of Pathology, Yale School of Medicine, New Haven, Connecticut., Wiesehöfer M; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., de Miguel FJ; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Liu Z; Department of Pathology, Yale School of Medicine, New Haven, Connecticut., Chan LH; Department of Pathology, Yale School of Medicine, New Haven, Connecticut., Choi J; Department of Genetics, Yale School of Medicine, New Haven, Connecticut., Melnick MA; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Arnal Estape A; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Walther Z; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Zhao D; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.; Yale Center for Genome Analysis (YCGA) Yale School of Medicine, New Haven, Connecticut., Lopez-Giraldez F; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.; Yale Center for Genome Analysis (YCGA) Yale School of Medicine, New Haven, Connecticut., Wurtz A; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Cai G; Department of Pathology, Yale School of Medicine, New Haven, Connecticut., Fan R; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.; Department of Biomedical Engineering, Yale School of Engineering and Applied Science, New Haven, Connecticut., Gettinger S; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut., Xiao A; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.; Department of Genetics, Yale School of Medicine, New Haven, Connecticut., Yan Q; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Homer R; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut., Nguyen DX; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut., Politi K; Department of Pathology, Yale School of Medicine, New Haven, Connecticut.; Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, Connecticut.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Apr 15; Vol. 84 (8), pp. 1303-1319.
DOI:	10.1158/0008-5472.CAN-23-0438
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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