Abstract LB_B26: Efficacy and tolerability of a novel pan-RAS inhibitor with a unique mechanism of selectivity in mouse models of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the U.S. This is frequently due to advanced disease at time of diagnosis as well as the high prevalence of KRAS driver mutations. Currently available targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutations in PDAC are KRAS-G12D, KRAS-G12V, and KRAS-G12R. Thus, the need for novel RAS-targeted therapeutics with efficacy in tumors with these more common mutations is of utmost urgency to reduce PDAC disease burden. Our novel class of pan-RAS inhibitors have unique biological and attractive drug-like properties. We synthesized an orally bioavailable prodrug, ADT-1004, which generates the active species, ADT-007, that inhibits growth of PDAC tumors. ADT-007 inhibits PDAC cell growth in vitro with IC50 as low as 2 nM regardless of RAS mutant allele, inhibits RAS activation, and downstream MAPK/AKT signaling. Differentiated normal epithelial cells, hepatic cells, and tumor cells with wild type RAS are insensitive to ADT-007 due to enzymatic detoxification providing unique selectivity for a pan-RAS inhibitor. ADT-1004 is well tolerated in vivo, producing sustained ADT-007 concentrations well above IC50 values in plasma. Daily oral ADT-1004 administration results in significant inhibiteion of tumor growth in both mouse orthotopic and PDX models of PDAC tumors accompanied by a reduction in RAS signaling. Citation Format: Adam B Keeton, Yulia Y Maxuitenko, Jeremy B Foote, Chung-Hui Huang, Kristy L Berry, Khalda Fadlalla, Ganji P Nagaraju, Bandi DS Reddy, Xi Chen, Bassel F El-Rayes, Donald J Buchsbaum, Gary A Piazza. Efficacy and tolerability of a novel pan-RAS inhibitor with a unique mechanism of selectivity in mouse models of pancreatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B26.