Abstract B062: Mutant Gnas confers resistance to KRAS inhibition via IL-33 in IPMN-derived PDAC
Kohki Oyama, Yuki Makino, Akiko Sagara, Bong Jun. Kim, Jimin Min, Albert Sohn, Peter Yu, Fredrik I. Thege, Anirban MaitraAbstract
Background:
Oncogenic mutations in KRAS and GNAS are major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), precursor lesions of pancreatic ductal adenocarcinoma (PDAC). We previously showed that pancreas-specific co-expression of Kras G12D and Gnas R201C in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-Gnas R201C) mice (“Kras;Gnas” mice) generates cystic lesions that recapitulate human IPMNs. Here, we investigated the mechanisms of resistance to KRAS inhibition in Kras;Gnas-driven IPMN/PDAC.
Methods:
Cell lines derived from murine Kras;Gnas-driven IPMN/PDAC tumors were used to assess sensitivity to MRTX1133 and RMC6236 by cell viability assays. Because IL-33 is markedly upregulated following doxycycline (Dox) -induced expression of mutant Gnas, we examined whether IL-33 knockout alters response to KRAS inhibition. Allograft transplantation models were used to evaluate the effects of mutant Gnas and IL-33 on sensitivity to MRTX1133 in vivo. For mechanistic analyses, we performed bulk RNA-seq of Kras;Gnas cells and scRNA-seq of pancreatic tissues from Kras;Gnas IL-33 WT and KO mice.
Results:
Dox-induced expression of mutant Gnas rendered Kras;Gnas cells less sensitive to MRTX1133 and RMC6236 than cells under Dox-negative condition. This effect was completely abolished by IL-33 knockout. In vivo, transplanted tumors in mice fed a normal diet showed significant regression following MRTX1133 treatment, whereas tumors in Dox-fed mice failed to respond, indicating that mutant Gnas confers resistance to KRAS inhibition. Notably, IL-33-deficient tumors regressed significantly even under Dox-fed conditions, demonstrating that IL-33 is required for mutant Gnas-mediated resistance. Transcriptomic analyses revealed that mutant Gnas promotes a shift toward a classical PDAC phenotype with reduced dependence on KRAS–MAPK signaling, providing a mechanistic basis for the altered drug response.
Conclusion:
Mutant Gnas reduces sensitivity to KRAS inhibition, at least in part, through IL33 and by promoting a shift toward a KRAS-MAPK-independent and classical PDAC phenotype. These findings identify IL-33 as a key mediator of resistance and a potential therapeutic target for enhancing the efficacy of KRAS-targeted therapies in pancreatic neoplasms.
Citation Format:
Kohki Oyama, Yuki Makino, Akiko Sagara, Bong Jun. Kim, Jimin Min, Albert Sohn, Peter Yu, Fredrik I. Thege, Anirban Maitra. Mutant Gnas confers resistance to KRAS inhibition via IL-33 in IPMN-derived PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B062.