Mutant Gnas confers resistance to KRAS inhibition via IL-33 in IPMN-derived PDAC (AACRPanCa 2026) - Oct 15, 2026 - Abstract #B062; "Here, we investigated the mechanisms of resistance to KRAS inhibition in Kras; Gnas-driven IPMN/PDAC.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...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."
Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • GNAS • IL33 • KRAS
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Kohki Oyama; Yuki Makino; Akiko Sagara; Bong Jun. Kim; Jimin Min; Albert Sohn; Peter Yu; Fredrik I. Thege; Anirban Maitra
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