Abstract 5915: ADT-1004: A promising pan-RAS inhibitor for targeting KRAS mutations in pancreatic ductal adenocarcinoma

Abstract Background/Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly challenging cancer with a dismal 5-year survival rate of under 12%. More than 90% of PDAC cases involve mutations in the GTPase KRAS. Unfortunately, existing drugs targeting the RAS family, like sotorasib, exclusively address the KRAS-G12C mutation, mainly found in NSCLC. In PDAC, most patients are diagnosed at advanced stages with unresectable tumors that exhibit various genetic mutations. Approximately 70% of these cases have KRAS-G12D mutations, often co-occurring with KRAS-G12V, KRAS-G12C, and KRAS-G12R mutations. This highlights the urgent need for innovative treatments that effectively address the complex mutation landscape in PDAC and avoid resistance mechanisms associated with mutant-specific or pan-KRAS inhibitors. Methods: KPC-Luc (1 × 105) and 2838C3-Luc (1. 5 × 105) PDAC cells carrying the KRAS-G12D mutation were injected into the pancreas of C57BL/6J mice. After one week, the mice were randomly divided into treatment groups (n = 7 per group) and received oral ADT-1004 at a dose of 40mg/kg body weight five times a week for four weeks. Tumor burden was assessed by bioluminescence signals using the IVIS Xenogen imaging system for patient-derived xenografts from PDAC patients with the KRAS-G12V mutation who were subcutaneously implanted in NSG mice. A week later, mice were randomized (n=7 per group) and treated orally with 40mg/kg of ADT-1004 five times a week for six weeks. Body weight and tumor size were measured twice weekly. Results: ADT-1004, a prodrug of ADT-007 that exhibits potent inhibitory effects on the proliferation of both human and murine RAS mutant PDAC cell lines with single-digit nM IC50 values, compared with µM IC50 in PDAC cells with WT RAS, was well tolerated in mice at a dose up to 175 mg/kg bid orally with sustained plasma levels of ADT-007 that exceeded IC50 values by 50-fold and even higher concentrations in pancreatic tumors. When administered orally at 40mg/kg body weight, ADT-1004 resulted in substantial growth inhibition of the KRAS-G12D and KRAS-G12V tumors, leading to profound tumor regression without any accompanying loss in body weight. ADT-1004 also displayed a significant inhibitory effect on ERK phosphorylation. Notably, this inhibition is effective regardless of the specific RAS mutational codon or isozyme, as it specifically targets activated RAS and disrupts downstream KRAS signaling pathways. Conclusion: These results highlight the promise of ADT-1004 as a potential breakthrough for treating PDAC. This novel pan-RAS inhibitor demonstrates potent inhibition of PDAC growth, irrespective of the specific KRAS mutation. Furthermore, it shows an excellent safety profile, with profound tumor regression and no impact on body weight in animal models. These findings open new possibilities for addressing the complex genetic landscape of PDAC. Citation Format: Dhana Sekhar Reddy Bandi, Purnachandra Nagaraju Ganji, Sujith Sarvesh, Yulia Maxuitenko, Jeremy B Foote, Adam B Keeton, Xi Chen, Donald Buchsbaum, Gary Piazza, Bassel El-Rayes. ADT-1004: A promising pan-RAS inhibitor for targeting KRAS mutations in pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5915.