Abstract 4392: A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance

ADT-007 is a novel reversible pan-RAS inhibitor with ultra-high potency and unique selectivity to inhibit the growth of cancer cells with mutant or activated RAS by blocking GTP activation of RAS. ADT-1004, an orally bioavailable prodrug of ADT-007, displayed robust antitumor activity in multiple mouse models of pancreatic ductal adenocarcinoma (PDAC), including PDX models harboring KRASG12D, KRASG12C, KRASG12V, and KRASG13Q mutations, at dosages approximately 9-fold below the maximum tolerated dose. Analysis of treated tumors revealed that ADT-1004 suppressed GTP-RAS and p-ERK levels and activated antitumor immunity. As evidence of target selectivity for mutant RAS, ADT-1004 suppressed the growth of KRASG12C MIA PaCa-2 tumors without affecting KRASWT BxPC-3 tumor growth. ADT-1004 displayed superior antitumor activity over sotorasib and adagrasib in a PDAC model involving MIA PaCa-2 cells that developed resistance to mutant-specific KRAS inhibitors. In vitro experiments show that ADT-007 potently inhibited the proliferation of cancer cell lines harboring mutations in K/N/H RAS without affecting the proliferation of cells with downstream BRAF mutations or cells from normal tissues. Cancer cell lines with RASWT but amplified RAS or upstream mutations in RTK or NF-1 were also highly sensitive to ADT-007 with low nM potency. ADT-007 reduced GTP-RAS levels from mutant KRAS and co-expressed RASWT isoforms under serum-free and EGF-stimulated conditions while inhibiting MAPK/AKT signaling to suppress MYC levels. Growth assays involving direct comparison of ADT-007 with mutant-specific KRASG12C inhibitors (sotorasib), pan-KRAS inhibitors (BI-2865), or other pan-RAS inhibitors (RMC-6236) revealed more complete cancer cell killing by ADT-007. In addition, colony formation assays showed near complete inhibition by ADT-007 but only partial inhibition by sotorasib, BI-2865, and RMC-6236. ADT-007 also inhibited the growth of RASWT cancer cells harboring amplified RAS with more extensive killing compared with BI-2865 and RMC-6236. Finally, cancer cell lines resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007 but showed resistance to MRTX849 and MRTX1133, respectively. These results show the unique advantages of ADT-1004 over mutant-specific KRAS, pan-KRAS, and other pan-RAS inhibitors to escape resistance that limits the efficacy of RAS inhibitors FDA-approved or in clinical trials. Citation Format: Gary A. Piazza, Dhana Sekhar Reddy Bandi, Ganji Purnachandra Nagaraju, Kristy Berry, Junwei Wang, Sindu Ramesh, Chung-Hui Huang, Upender Manne, Xi Chen, Jeremy B. Foote, Adam B. Keeton, Yulia Y. Maxuitenko, Donald J. Buchsbaum, Bassel F. El Rayes. A 1st in class pan-RAS inhibitor with robust antitumor activity in PDAC models and advantages over other RAS inhibitors to escape resistance [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 4392.