2. Academic Validation
  3. Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer

  • bioRxiv. 2026 Apr 21:2026.04.18.719329. doi: 10.64898/2026.04.18.719329.
Wen-Hsuan Chang 1,  Alec J Vaughan 2 3,  Addison G Stamey 1,  Mariana Mancini 2 3 4,  Makiko Hayashi 2 3,  Runying Yang 1,  Ryan Robb 5,  Daniel Andrussier 3,  Jeffrey A Klomp 1,  Andrew M Waters 1,  Antje Schaefer 1,  Brian M Wolpin 6,  Kirsten L Bryant 1 5,  Adrienne D Cox 1 5 7,  Fernando Moreira Simabuco 4,  Kwok-Kin Wong 3,  Andrew J Aguirre 6 8 9 10,  Clint A Stalnecker 1 11,  Thales Papagiannakopoulos 2 3,  Channing J Der 1 5
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 2 Department of Pathology, NYU Langone Health, New York, New York.
  • 3 Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, New York.
  • 4 Department of Biochemistry, Federal University of São Paulo, São Paulo, Brazil.
  • 5 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 7 Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 8 The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
  • 9 Harvard Medical School, Boston, Massachusetts.
  • 10 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
  • 11 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
PMID: 42079131 DOI: 10.64898/2026.04.18.719329
Abstract

The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRASG12D-selective inhibitor MRTX1133 and the Ras(ON) multi-selective inhibitor RMC-7977 in pancreatic Cancer models. RNA-sequencing analyses revealed a KEAP1 KO 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.

Figures
Products