American Association for Cancer Research
Browse
can-23-0438_figure_s5_suppsf5.pdf (3.1 MB)

Figure S5 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts

Download (3.1 MB)
journal contribution
posted on 2024-04-15, 07:22 authored by 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

Characterization of mutant EGFR lung cancer PDXs at single-cell resolution. Workflow for scRNA-seq on PDXs and single cell data for an additional PDX.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

History

ARTICLE 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. 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

Usage metrics

    Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC