Abstract B005: ADT-030, a novel PDE10 inhibitor that blocks RAS and β-catenin signaling with robust and durable antitumor activity and potential to mitigate resistance and on-target toxicities of monospecific RAS inhibitors
Multiple cancers arise from co-occurring mutations that activate RAS/MAPK and Wnt/β-catenin signaling pathways, which cooperate to drive tumorigenesis, metastasis, and drug resistance. A dual inhibitor of RAS and β-catenin signaling may offer a more effective therapeutic strategy compared with monospecific inhibitors of RAS or β-catenin currently in clinical trials for such cancers. We previously reported that the cGMP-degrading phosphodiesterase 10A (PDE10) isozyme is overexpressed in various cancers and that pharmacological inhibition or genetic silencing of PDE10 selectively suppresses the growth of cancer cells with high PDE10 expression relative to normal cells with low PDE10 levels. Because conventional PDE10 inhibitors developed for CNS disorders are rapidly metabolized and cause sedation, we developed ADT-030, a PDE10 inhibitor optimized for systemic bioavailability. ADT-030 potently inhibited recombinant PDE10 at concentrations that bind PDE10 in cells. Similar concentrations activated cGMP-dependent PKG, phosphorylated and degraded the oncogenic pool of β-catenin, and suppressed EGF-stimulated RAS-mediated MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. Notably, cancer cells that developed cross-resistance to pan-RAS, pan-KRAS, and mutant-specific KRAS inhibitors retained full sensitivity to ADT-030. Oral administration of ADT-030 demonstrated robust antitumor activity across multiple mouse tumor models (orthotopic, xenograft, PDX, and chemically induced) and cancer types. KRAS-mutant pancreatic and lung cancer models were particularly sensitive to ADT-030, resulting in tumor regression, metastasis inhibition, and durable efficacy that persisted well beyond the treatment period. ADT-030 also inhibited tumor growth in a PDX model of adrenocortical carcinoma, a cancer driven by CTNNB1 mutations. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment, characterized by selective induction of apoptosis in MDSC cells and increased tumor infiltration by CD8+ T cells and NK cells. The activity of ADT-030 was comparable to that of chemotherapy and immune checkpoint inhibitors, while combinations showed greater efficacy. These results support IND-enabling studies of ADT-030 as a monotherapy or in combination with standard-of-care treatments for patients with a broad range of RAS-driven cancers, and especially for patients who relapsed after RAS inhibitor treatment. Because PDE10 has low expression and no known physiological function outside the CNS, ADT-030 is not expected to cause on-target toxicities associated with monospecific RAS or β-catenin inhibitors. Xi Chen, Dhana S.R. Bandi, Ganji P. Nagaraju, Junwei Wang, Sindhu Ramesh, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Gang Zhou, Fokhrul Hossain, Suresh Kumar, Nitin Roper, Jeremy B. Foote, Donald J. Buchsbaum, Adam B. Keeton, Yulia Y. Maxuitenko, Bassel F. El-Rayes, Gary A. Piazza. ADT-030, a novel PDE10 inhibitor that blocks RAS and β-catenin signaling with robust and durable antitumor activity and potential to mitigate resistance and on-target toxicities of monospecific 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 B005.