A classical epithelial state drives acute resistance to KRAS inhibition in pancreatic cancer Journal Article


Authors: Singhal, A.; Styers, H. C.; Rub, J.; Li, Z.; Torborg, S. R.; Kim, J. Y.; Grbovic-Huezo, O.; Feng, H. J.; Tarcan, Z. C.; Ozkan, H. S.; Hallin, J.; Basturk, O.; Yaeger, R.; Christensen, J. G.; Betel, D.; Yan, Y.; Chio, I. I. C.; de Stanchina, E.; Tammela, T.
Article Title: A classical epithelial state drives acute resistance to KRAS inhibition in pancreatic cancer
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
Keywords: efficacy; models; addiction; ductal adenocarcinoma; subtypes; kras(g12d)
Journal Title: Cancer Discovery
Volume: 14
Issue: 11
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2024-11-01
Start Page: 2122
End Page: 2134
Language: English
ACCESSION: WOS:001349605800024
DOI: 10.1158/2159-8290.Cd-24-0740
PROVIDER: wos
PMCID: PMC11624508
PUBMED: 38975873
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Tuomas Tammela -- Source: Wos
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MSK Authors
  1. Olca Basturk
    353 Basturk
  2. Rona Denit Yaeger
    323 Yaeger
  3. Tuomas Tammela
    23 Tammela
  4. Yan Yan
    5 Yan
  5. Zhuxuan Li
    4 Li
  6. Zeynep Cagla Tarcan
    23 Tarcan
  7. Hannah Styers
    1 Styers
  8. Jonathan Rub
    1 Rub
  9. Jung Yun Kim
    1 Kim