EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy

Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.

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Publication Details

Journal
JCI Insight
Published
2026-01-22
DOI
https://doi.org/10.1172/jci.insight.197008
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
0.00

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EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy

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EGFR-mutant transformed small cell lung cancer harbors intratumoral heterogeneity targetable with MEK inhibitor combination therapy

Michael Yevgeniy Tolstorukov, Atsuko Ogino, Emily S. Chambers, Rubii M. Tamen, Camilla L. Christensen, Oliver R. Mikse, Benjamin F. Springer, Hideo Watanabe, Benjamin K. Eschle, Anika E. Adeni, Xinmeng Jasmine Mu, Cameron Messier, Jeffrey J. Okoro, Sudeepa Syamala, Cloud Peter Paweletz, Matthew G. Oser, Tran C. Thai, Matthew Aaron Booker, Patrick H. Lizotte, Prafulla C. Gokhale, Amir Vajdi, Navin R. Mahadevan, Cheng Xu, Israel Canadas, Man Xu, Kenneth Ngo, Henry W. Long, Pasi A. Jänne, Geoffrey R. Oxnard, David A. Barbie, Paloma Cejas, Stephen Wang
article en

Abstract

Small cell lung cancer (SCLC) transformation is an incompletely characterized mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant cancers, limiting development of optimal treatment approaches. Through single-cell RNA sequencing of malignant pleural effusions from patients who underwent SCLC transformation, we identified heterogeneity and diversity, including distinct neuroendocrine (NE) and mesenchymal non-NE cancer cell subsets, which were maintained in patient-derived cell lines. We demonstrate that EZH2 regulates EGFR expression in NE cells where EGFR expression is silenced at baseline. Although neither epigenetic derepression nor exogenous overexpression of mutant EGFR sensitized the cells to EGFR inhibition, non-NE cells exhibited selective sensitivity to MEK inhibitors. Combined MEK inhibitor and chemotherapy effectively inhibited growth of both NE and non-NE cells in vitro and in vivo. Our findings demonstrate that EGFR-mutant SCLC is composed of mixed cell states with distinct therapeutic vulnerabilities and offer a therapeutic strategy to target tumor heterogeneity in highly plastic and treatment-resistant malignancies such as transformed SCLC.

JCI InsightVol. 11(2)
Broad Institute (US), Brigham and Women's Hospital (US), Fox Chase Cancer Center (US), Harvard University (US), St. Catherine University (US), Parker Institute for Cancer Immunotherapy (US), Dana-Farber Cancer Institute (US), Tisch Hospital (US), Epigenomics (Germany) (DE), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Defense, Dana-Farber/Harvard Cancer Center, National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 81%
Lung Cancer Research Studies
DOIOpen Access PDFOpenAlex
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