Abstract 6390: Identification of novel pan-KRAS mutation inhibitor shows significant efficacy in pancreatic cancer with no toxicity, offering hope beyond current therapies

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to treat, with current therapies providing a median survival of just six months. The intrinsic chemoresistance and genetic heterogeneity of PDAC tumors complicate the development of effective targeted therapies. Approximately 90% of PDAC cases harbor KRAS mutations, which drive tumor initiation and progression, making KRAS a critical therapeutic target. Although the FDA has approved two KRAS inhibitors (Sotorasib and Adagrasib) for lung cancer, these drugs specifically target the KRAS-G12C mutation, found in only 2% of PDAC cases. Most PDAC tumors carry other KRAS mutations, particularly KRAS-G12D, leaving patients with limited targeted treatment options. To address this, we synthesized 21 compounds and identified 3E as a novel pan-KRAS inhibitor targeting KRAS-G12D, KRAS-G12C, and KRAS-G12S. Kaplan-Meier analysis of the TCGA PDAC database (n=177, p=0.00036) showed that elevated KRAS expression correlates with shorter survival, highlighting KRAS's role in PDAC progression. In vitro, treatment with 3E inhibited KRAS signaling in PDAC cells (PANC1, Miapaca-2) and KPC transgenic cells, as indicated by p-ERK suppression. 3E significantly reduced cell proliferation, migration, and invasion. Clonogenic assays demonstrated that 3E was more effective than Adagrasib and Salirasib (a non-specific RAS inhibitor in Phase II trials) at inhibiting PDAC cell growth. Moreover, 3E showed synergy with gemcitabine, a first-line chemotherapeutic agent for PDAC, enhancing its antiproliferative effects. In vivo, systemic delivery of 3E encapsulated in single lipid nanoparticles (SLNP) delayed tumor growth in PDAC xenograft and KPC transgenic mouse models without toxicity, as shown by blood chemistry markers. Tumor analysis after 3E treatment revealed reduced intra-tumoral proliferation (Ki-67 by IHC) and increased apoptosis (TUNEL assay). These findings suggest that 3E is a promising therapeutic candidate for KRAS-driven PDAC and other cancers. Its superior efficacy over FDA-approved KRAS inhibitors and synergy with gemcitabine support its clinical potential as a novel treatment approach for this aggressive cancer. Citation Format: Pinar Atalay, Asli Ture, Nermin Kahraman, Izabela Fokt, Waldemar Priebe, Erdem Buyukbingol, Bulent Ozpolat. Identification of novel pan-KRAS mutation inhibitor shows significant efficacy in pancreatic cancer with no toxicity, offering hope beyond current therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6390.