Abstract A052: ADT-030: A novel PDE10 inhibitor with robust and durable antitumor activity and the capacity to overcome resistance common to RAS inhibitors through dual blockade of RAS and β-catenin signaling

Abstract Resistance to RAS inhibitors resulting from compensatory activation of MAPK/AKT signaling by unchecked non-mutant RAS isoforms limits their use and efficacy. Secondary RAS mutations or aberrant activation of other oncogenic pathways (e.g., Wnt/APC/β-catenin) can also lead to resistance, particularly in the case of colorectal cancer. We and others have reported that the cyclic nucleotide-phosphodiesterase 10A (PDE10) isozyme is overexpressed in multiple cancer cell lines as well as patient tumors but has low expression and no known function in tissues outside the CNS. PDE10-specific inhibitors and gene silencing were found to selectively inhibit the growth of cancer cells. PDE10 inhibitors developed to treat CNS disorders achieve high brain levels but low levels in peripheral tissues. Thus, we designed a novel, orally bioavailable PDE10 inhibitor, ADT-030, that achieves high systemic levels exceeding those required to inhibit recombinant PDE10 and growth but lacks the major side effect (sedation) caused by conventional PDE10 inhibitors. ADT-030 bound to PDE10 and activated protein kinase G in cancer cells within the same concentration range that inhibited proliferation and induced apoptosis of a large panel of histologically diverse cancer cell lines. These effects occurred within the same concentration range at which ADT-030 inhibited RAS-mediated MAPK/AKT signaling and selectively degraded the oncogenic (transcriptionally active) pool of β-catenin. Notably, cancer cell lines that developed resistance to pan-RAS, pan-KRAS, or mutant-specific KRAS inhibitors retained full sensitivity to ADT-030. ADT-030 strongly inhibited tumor growth in both immune-competent and immune-deficient mouse models of colon, lung, breast, and pancreatic cancer at dosages that were well tolerated. Pancreatic cancer models were particularly sensitive to ADT-030, resulting in tumor regression, inhibition of metastasis, and prolonged survival. Notably, the antitumor activity of ADT-030 was superior to that of standard-of-care (gemcitabine + nab-paclitaxel) treatment for pancreatic cancer patients, and the combined treatment of ADT-030 and chemotherapy resulted in even greater activity in an orthotopic mouse model of pancreatic cancer. ADT-030 also increased survival and inhibited metastasis in mouse models of lung cancer with a durable response that persisted well beyond the treatment period, resulting in cures. ADT-030 also enhanced the antitumor activity of chemotherapy (paclitaxel) and immune checkpoint inhibitors in mouse models of lung, colon, and breast cancer. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment, characterized by the selective induction of apoptosis in myeloid-derived suppressor cells (MDSC), while increasing tumor infiltration by CD8+ T cells and natural killer cells. These results show that ADT-030 has potential advantages over direct-acting RAS inhibitors, supporting the development of ADT-030 as a monotherapy or combined with standard-of-care treatment for RAS-driven cancers. Citation Format: Gary A. Piazza, Dhana Sekhar Reddy Bandi, Veronica Ramirez-Alcantara, Ganji Purnachandra Nagaraju, Junwei Wang, Sindhu Ramesh, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Md Yeashin Gazi, Xi Chen, Jeremy B. Foote, Adam B. Keeton, Yulia Y. Maxuitenko, Donald J. Buchsbaum, Fokhrul Hossain, Gang Zhou, Bassel F. El-Rayes. ADT-030: A novel PDE10 inhibitor with robust and durable antitumor activity and the capacity to overcome resistance common to RAS inhibitors through dual blockade of RAS and β-catenin signaling [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 A052.