Supplementary Table 1 from A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer

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posted on 2024-11-01, 07:41 authored by Anupriya Singhal, Hannah C. Styers, Jonathan Rub, Zhuxuan Li, Stefan R. Torborg, Jung Yun Kim, Olivera Grbovic-Huezo, Huijin Feng, Zeynep Cagla Tarcan, Hulya Sahin Ozkan, Jill Hallin, Olca Basturk, Rona Yaeger, James G. Christensen, Doron Betel, Yan Yan, Iok In Christine Chio, Elisa de Stanchina, Tuomas Tammela

Supplementary Table 1 includes gene set enrichment analysis (GSEA) of KPF mouse PDAC cells comparing MRTX1133-treated vs. vehicle-treated classical and basal cells

Funding

American Society of Clinical Oncology (ASCO)

Break Through Cancer (BTC)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with basal dominance associating with chemoresistance and a dismal prognosis. Targeting oncogenic KRAS, the primary driver of pancreatic cancer, shows early promise in clinical trials, but efficacy is limited by acquired resistance. Using genetically engineered mouse models and patient-derived xenografts, we find that basal PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent and bioluminescent reporter systems, we longitudinally track cell-state dynamics in vivo and reveal a rapid, KRAS inhibitor–induced enrichment of the classical state. Lineage tracing uncovers that these enriched classical PDAC cells are a reservoir for disease relapse. Genetic or chemotherapy-mediated ablation of the classical cell state is synergistic with KRAS inhibition, providing a preclinical proof of concept for this therapeutic strategy. Our findings motivate combining classical state–directed therapies with KRAS inhibitors to deepen responses and counteract resistance in pancreatic cancer.Significance: KRAS inhibitors hold promise in pancreatic cancer, but responses are limited by acquired resistance. We find that a classical epithelial cancer cell state is acutely resistant to KRAS inhibition and serves as a reservoir for disease relapse. Targeting the classical state alongside KRAS inhibition deepens responses, revealing a potent therapeutic strategy.See related commentary by Marasco and Misale, p. 2018

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Keywords

Oncogenes & Tumor Suppressors Kras

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