Abstract B014: A mechanistically distinct pan-RAS inhibitor, ADT-007, with robust antitumor activity evades resistance common to mutant-specific and pan-RAS Inhibitors

Abstract RAS mutations 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. RAS inhibitors recently approved by the FDA or in clinical trials appear to have limited efficacy due to the emergence of acquired resistance. We recently described a mechanistically distinct pan-RAS inhibitor, ADT-007, that selectively kills cancer cells harboring activated RAS, whether driven by oncogenic mutations or activation by upstream receptor tyrosine kinase signaling. ADT-007 potently inhibited the growth of an array of cancer cell lines harboring various RAS mutations or activated RAS with low nM IC50 values. In contrast, cancer cells with downstream RAF mutations or cells of normal tissues were essentially insensitive. Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS to block GTP loading and activation of the MAPK/AKT signaling pathway, resulting in mitotic arrest and apoptosis. ADT-007’s unique selectivity was attributed to metabolic detoxification by glucuronidation from UDP-glucuronosyltransferases (UGTs), which we found to be enriched in normal cells compared with RAS-mutant cancer cells. Notably, ADT-007 induced apoptosis and caused nearly complete inhibition of colony formation in the Mia-PaCa-2 human pancreatic cell line, whereas a pan-KRAS inhibitor, BI-2865, and a pan-RAS inhibitor, RMC-6236, did not induce apoptosis but only suppressed proliferation and marginally inhibited colony formation under the same conditions. BI-2865 and RMC-6236 inhibited MAPK signaling in the sensitive lines but did not inhibit signaling in the resistant lines. Furthermore, RAS mutant colon and pancreatic cancer cells did not develop resistance to ADT-007 under chronic exposure, in contrast to sotorasib, BI-2865, and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor to which they were exposed. Moreover, the resistant cell lines also exhibited cross-resistance to mechanistically distinct classes of RAS inhibitors, including pan-KRAS, pan-RAS, and allele-specific KRAS inhibitors, but not to ADT-007 or a second-generation inhibitor, ADT-030. These observations suggest a shared mechanism of acquired resistance that may limit the efficacy of currently known RAS inhibitors (approved or in development). 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. Consistent with in vitro experiments, ADT-1004 displayed superior efficacy to sotorasib or adagrasib in a xenograft model using a resistant MIA-PaCa-2 tumor model. These results support further development of ADT-1004 for a broad range of RAS-mutant cancers. Citation Format: Junwei Wang, Xi Chen, Sindhu Ramesh, Jeremy B. Foote, Chung-Hui Huang, Kristy L. Berry, Khalda Fadlalla, Bandi D. S. Reddy, Ganji P. Nagaraju, Elmar Nurmemmedov, Ivan Babic, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Adam B. Keeton, Bassel F. El-Rayes, Gary A. Piazza. A mechanistically distinct pan-RAS inhibitor, ADT-007, with robust antitumor activity evades resistance common to mutant-specific and pan-RAS Inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B014.