Abstract A089: ADT-1004: A mechanistically distinct pan-RAS inhibitor with the potential to escape resistance and mitigate on-target toxicities that limit efficacy and safety of other RAS inhibitors
Gain-of-function mutations in RAS genes are the most prevalent oncogenic mutations responsible for about one-third of all human malignancies. Despite decades of research, direct targeting of RAS remains a major clinical challenge, as FDA-approved RAS inhibitors and those in clinical trials have limited efficacy and on-target toxicities. We recently characterized a mechanistically distinct pan-RAS inhibitor, ADT-007, with highly potent and selective growth-inhibitory activity against cancer cells with mutant or activated RAS (Cancer Res, 2025). Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS, blocking GTP loading and RAS activation, leading to mitotic arrest and apoptosis. Notably, ADT-007 induced apoptosis and caused near-complete inhibition of colony formation in KRAS mutant pancreatic cancer cells, whereas the pan-KRAS inhibitor, BI-2865, and the pan-RAS inhibitor, RMC-6236, did not induce apoptosis and marginally inhibited colony formation when tested under the same conditions at 10x growth IC50 values. In addition, KRAS mutant cancer cell lines did not develop resistance to ADT-007 under chronic exposure, in contrast to BI-2865 and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor that induced resistance. Interestingly, the RMC-6236-resistant cells exhibited cross-resistance to BI-2865 and vice versa, as well as cross-resistance to allele-specific KRAS inhibitors, but not to ADT-007. The RAS selectivity of ADT-007 involves a unique metabolic mechanism of deactivation by UDP-glucuronosyltransferases (UGTs), which are expressed in normal cells but not in KRAS-mutant cancer cells. An orally bioavailable prodrug of ADT-007, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels (Mol Cancer, 2025). ADT-1004 displayed superior efficacy compared with sotorasib or adagrasib in a xenograft model using a resistant pancreatic cancer cell line. These findings support the further development of ADT-1004, which holds promise for broad and durable efficacy against RAS-driven cancers, with the potential to overcome resistance and on-target toxicities. Junwei Wang, Xi Chen, Bandi D. S. Reddy, Ganji P. Nagaraju, Sindhu Ramesh, Austin Moore, Thomas Holmes, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Jeremy B. Foote, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Adam B. Keeton, Bassel F. El-Rayes, Gary A. Piazza. ADT-1004: A mechanistically distinct pan-RAS inhibitor with the potential to escape resistance and mitigate on-target toxicities that limit efficacy and safety of other RAS inhibitors [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A089.