LAUSR

Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer death in the U.S. with only about a 10% five-year survival rate and an estimated 60,000 deaths/year by 2030. Poor survival is frequently due to advanced disease at the time of diagnosis, as well as the high prevalence of KRAS driver mutations. Currently, approved KRAS-targeted therapeutics are designed to covalently inactivate only KRAS-G12C mutants, whereas the most common mutations in PDA 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 PDA disease burden. We have synthesized a novel chemical class of pan-RAS inhibitors with unique biological properties and attractive drug-like properties. As a prodrug, ADT-1004, generates an active metabolite, ADT-007, that potently inhibits the growth of human and murine PDA cell lines in vitro with single-digit nM IC50 irrespective of specific RAS mutational codon or isozyme by inhibiting activated RAS and signaling downstream of KRAS (ERK1/2 and AKT phosphorylation). ADT-1004 is well tolerated with no discernable toxicity at oral dosages of up to 175 mg/kg bid. Pharmacokinetic studies demonstrated that ADT-1004 produces sustained plasma concentrations of ADT-007 ~50-fold above IC50 values, with even higher concentrations in both subcutaneous and orthotopic pancreatic tumors. Once daily oral administration of ADT-1004 significantly inhibited the growth of orthotopically implanted PDA tumors with a corresponding reduction in RAS/MAPK signaling. ADT-1004 represents a 1st-in-class pan-RAS inhibitor with potential advantages over mutant-specific KRAS inhibitors for greater efficacy and ability to avert mechanisms of resistance. These data support future clinical trials of ADT-1004 as a monotherapy for the treatment of patients with PDA regardless of the underlying mutation. Citation Format: Yulia Y. Maxuitenko, Jeremy B. Foote, Adam B. Keeton, Xi Chen, Kristy Berry, Khalda Fadlalla, Jacob Valiyaveettil, Chung-Hui Huang, Austin M. Moore, Emily C. Graff, Ganji P. Nagaraju, Julienne L. Carstens, Bassel F. El-Rayes, Donald J. Buchsbaum, Gary A. Piazza. Antitumor activity of 1st-in-class pan-RAS inhibitor ADT-1004 in mouse models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB322.