Abstract P87: Drug-induced Hyperactivation of the oncogene KRAS induces ferroptosis in G12-mutant KRAS Pancreatic Ductal Adenocarcinoma (PDAC)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a dismal prognosis and limited treatment options. With ∼90% of PDAC cases harboring KRAS mutations, targeting KRAS has been a major therapeutic focus. However, its small size and high affinity for GTP present challenges for direct inhibition. Our lab previously identified Merodantoin (C1), a compound that paradoxically hyperactivates mutant KRAS and induces apoptosis, particularly in colon cancer. This study explores the efficacy and mechanism of C1 in KRAS-mutant PDAC. We treated PDAC cell lines and patient-derived organoids (PDOs) with C1 and assessed cell viability, ROS production, iron accumulation, and protein expression via flow cytometry and Western blotting. C1 exhibited selective cytotoxicity toward PDAC cells harboring KRAS G12C/G12D mutations, sparing wild-type KRAS cells. Mechanistically, C1 elevated both total and mitochondrial ROS and labile Fe2+ in all cells, but only induced lipid peroxidation and ferroptosis in KRAS G12-mutant cells. Ferroptosis inhibitors (ferrostatin-1, liproxstatin) and iron chelator (DFO) rescued these effects. C1 suppressed the GSH-antioxidant system selectively in mutant KRAS cells by reducing cystine uptake, GPX4 expression, and GSH levels in MIA PaCa-2 and PANC-1, but not in wild-type BxPC-3 cells. Resistance in BxPC-3 was linked to higher basal GPX4 levels. Silencing GPX4 sensitized BxPC-3 cells to C1, confirming its role in resistance. Furthermore, KRAS knockdown or inhibition (e.g., sotorasib) abrogated C1-induced ferroptosis, confirming KRAS as an upstream driver of this death pathway. These findings were validated in PDOs, with ongoing work in mouse models. Overall, this study presents C1 as a novel therapeutic agent for KRAS-mutant PDAC and introduces the concept of hyperactivating oncogenic KRAS to selectively induce ferroptotic cancer cell death. Citation Format: Haiyuxin Zhu, Kartini Iskandar, Nur Syafiqah Binte Sulaiman, Benedict Joseph, Anne-sophie Armand, Franck Oury, Shazib Pervaiz. Drug-induced Hyperactivation of the oncogene KRAS induces ferroptosis in G12-mutant KRAS Pancreatic Ductal Adenocarcinoma (PDAC) [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P87.