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

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 Lopez-Giraldez, Anna Wurtz, Guoping Cai, Rong Fan, Scott Gettinger, Andrew Xiao, Qin Yan, Robert Homer, Don X. Nguyen, Katerina Politi

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1303-1319
Number of pages17
JournalCancer Research
Volume84
Issue number8
DOIs
Publication statusPublished - 2024 Apr 15

Bibliographical note

Publisher Copyright:
©2024 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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