A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer
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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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Lineage plasticity is a critical mechanism of non-genetic resistance to KRAS-targeted therapies in NSCLC and PDAC.
“Lineage plasticity has emerged as a critical mechanism of non-genetic resistance to KRAS-targeted therapies in NSCLC and PDAC.27–31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [31]
The Results (‘Classical PDAC cells give rise to disease relapse’; page unavailable) show that classical PDAC cells survive KRAS inhibition, give rise to other cell states, and contribute to relapse. The Discussion says this phenotypic shift mediates resistance in PDAC. It mentions a shift toward alveolar identity in lung adenocarcinoma but does not establish lineage plasticity as a resistance mechanism in NSCLC, so it supports the PDAC portion of the sentence, not the whole claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredLineage plasticity has an established role in resistance to KRAS-targeted therapies.
“Despite the established role of lineage plasticity in resistance to KRAS-targeted therapies,26–31 effective therapeutic interventions targeting drivers of lineage plasticity remain lacking.”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [31]
Transition into a classical state is observed in PDAC cells surviving KRAS-targeted therapy.
“Differentiation into alveolar type 1 (AT1)-like,26 squamous,27,28 as well as mucinous states29 has been implicated to contribute to KRAS inhibitor tolerance in lung adenocarcinoma, whereas transition into a classical state is observed in PDAC cells surviving KRAS-targeted therapy.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [31]
Pancreatic cancer cells adopt a classical epithelial state to bypass KRAS inhibition.
“In NSCLC, KRAS-mutant tumors evade therapy through transition into AT1-like,29 squamous,27,28 or mucinous states,29 while pancreatic cancer cells adopt a classical epithelial state to bypass KRAS inhibition.30,31”
From Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer (2026) · cites this paper as [31]
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- Authors
- Singhal, A., Styers, H. C., Rub, J., Li, Z., Torborg, S. R., Kim, J. Y., Grbovic-Huezo, O., Feng, H., Tarcan, Z. C., Sahin Ozkan, H., Hallin, J., Basturk, O., Yaeger, R., Christensen, J. G., Betel, D., Yan, Y., Chio, I. I. C., de Stanchina, E., & Tammela, T.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Columbia University Irving Medical Center (US)
- 2David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, New York, New York.
- Mirati Therapeutics (United States) (US)
- Weill Cornell Medicine (US)
- 1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Tammela, Tuomas
- ORCID
- Venue
- Cancer Discovery
- Published
- 2024-07-05
- Volume
- 14
- Issue
- 11
- Pages
- 2122-2134
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC11624508
- OpenAlex
- W4400416899
- Semantic Scholar
- 04662024790cb8192cdf2a7ce3c66046d31ffca3
- Cited by
- 84
- References
- 46
- Citations by year
- 2026: 41 · 2025: 36 · 2024: 7
- FWCI
- 14.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Society of Clinical Oncology
- Break Through Cancer
- National Cancer Institute (R37-CA244911, K12 CA184746, P50 CA257881-01A1, P30 CA08748)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- pancreatic ductal adenocarcinoma, KRAS inhibitors, acquired drug resistance, intratumoral heterogeneity, recurrence, lineage tracing, combination therapy, KRAS inhibition
- MeSH terms
- Animals, Humans, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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