Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer
transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors. SIGNIFICANCE: loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.
Authors
- Wen-Hsuan Chang (ORCID: https://orcid.org/0000-0002-5751-6345)
- Makiko Hayashi (ORCID: https://orcid.org/0000-0002-9189-0058)
- Kwok‐Kin Wong (ORCID: https://orcid.org/0000-0001-6323-235X)
- Andrew M. Waters (ORCID: https://orcid.org/0000-0002-6058-5878)
- Antje Schaefer (ORCID: https://orcid.org/0000-0002-2716-9899)
- Ryan Robb (ORCID: https://orcid.org/0000-0001-7661-7902)
- Brian M. Wolpin (ORCID: https://orcid.org/0000-0002-0455-1032)
- M. Mancini
- Jeffrey A. Klomp (ORCID: https://orcid.org/0000-0002-5243-6987)
- Thales Papagiannakopoulos (ORCID: https://orcid.org/0000-0002-2251-1624)
- Fernando Moreira Simabuco (ORCID: https://orcid.org/0000-0002-1672-9686)
- Kirsten L. Bryant (ORCID: https://orcid.org/0000-0003-4026-0942)
- Runying Yang (ORCID: https://orcid.org/0000-0002-5983-9439)
- Addison G. Stamey
- Alec Vaughan (ORCID: https://orcid.org/0000-0002-0154-8911)
- Daniel Andrussier (ORCID: https://orcid.org/0009-0003-4966-5281)
- Channing J Der
- Adrienne D Cox
- Andrew J Aguirre
- Clint A Stalnecker
Institutions
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- NYU Langone Health (US)
- Dana-Farber Cancer Institute (US)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-21
- DOI
- https://doi.org/10.64898/2026.04.18.719329
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Hale Family Center for Pancreatic Cancer Research
- U.S. Department of Defense
- American Cancer Society
- Pancreatic Cancer Action Network
- Lustgarten Foundation
- Break Through Cancer
- Sky Foundation
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Cancer Institute