Abstract 6767: Defining a molecular signature for KEAP1-NRF2 mediated resistance to KRAS inhibition in KRAS-mutant pancreatic and lung cancer

Abstract Mutational activation of KRAS is critical for driving the tumorigenic growth of pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD). Recent approval of inhibitors of one KRAS mutation (G12C) supports the therapeutic value of targeting mutant KRAS in PDAC and LUAD. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. With resistance mechanisms still incompletely established, we performed a CRISPR loss-of-function screen to identify genes that modulate the sensitivity of PDAC cells to KRAS inhibition. We determined that loss of KEAP1 and activation of the transcription factor NRF2 drove resistance to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977. RNA-sequencing analyses revealed that KEAP1 loss protected cancer cells from oxidative stress and cell cycle arrest induced by KRAS inhibition. Building upon our transcriptomic analyses, we established a PDAC KEAP1-deficient (PKD) gene signature. The PKD signature was prevalent in preclinical models and patients insensitive to KRAS inhibitor treatment. This signature was also distinct from transcriptional changes associated with other mechanisms driving KRAS inhibitor resistance (ERK, MYC, and YAP/TAZ-TEAD). Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the clinical candidate glutamine antagonist DRP-104 (sirpiglenastat) strongly enhanced KRAS inhibitor-mediated growth suppression in KRAS-mutant PDAC and NSCLC tumors in vivo. In summary, our studies established a gene signature for KEAP1 loss-driven resistance and validated a therapeutic strategy to overcome KEAP1-NRF2-driven RAS inhibitor resistance. Citation Format: Wen-Hsuan Chang, Alec J. Vaughan, Mariana Mancini, Addison G. Stamey, Makiko Hayashi, Runying Yang, Ryan Robb, Jeffrey A. Klomp, Andrew M. Waters, Antje Schaefer, Daniel Andrussier, Kirsten L. Bryant, Adrienne D. Cox, Fernando M. Simabuco, Andrew J. Aguirre, Kwok-Kin Wong, Clint A. Stalnecker, Thales Papagiannakopoulos, Channing J. Der. Defining a molecular signature for KEAP1-NRF2 mediated resistance to KRAS inhibition in KRAS-mutant pancreatic and lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6767.