Abstract B036: A novel PDE10 inhibitor that blocks RAS and β-catenin signaling and enhances tumor immunogenicity with robust activity to inhibit tumor growth and metastasis

Abstract Aberrant activation of RAS signaling due to gain-of-function mutations in RAS or upstream receptor tyrosine kinases, as well as RAS gene amplification, are key drivers of most human cancers and contribute to drug resistance. Co-occurring mutations in APC/β-catenin pathway components, often occurring in gastrointestinal and other solid tumors, also play a crucial role in malignant progression and drug resistance. Phosphodiesterase 10A (PDE10) is highly expressed in such cancers but has low expression in normal tissues outside the CNS and no known physiological function. PDE10 is essential for cancer cell proliferation and survival based on experiments using isozyme-specific inhibitors and genetic KD/KO approaches. Here we describe a novel PDE10 inhibitor, ADT-030, that inhibited cGMP hydrolysis by recombinant PDE10; bound PDE10 in intact cells as determined by cellular thermal stability assays; and induced cGMP/PKG signaling in cancer cells, all of which occurred at concentrations that inhibited the proliferation and induced apoptosis of cancer cells. ADT-030 also induced degradation of oncogenic β-catenin and blocked RAS activation and MAPK/AKT signaling within the same concentration range as PDE10 inhibition. Cancer cells resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-030 in growth assays. Oral administration of ADT-030 strongly inhibited tumor growth at doses without discernible toxicity in mouse tumor models of colon, lung, breast, and pancreatic cancer. Notably, ADT-030 caused tumor regression in patient-derived xenograft mouse models of pancreatic cancer and increased survival in an orthotopic mouse model of lung cancer, resulting in “cures” long after stopping treatment. ADT-030 also inhibited metastasis in pancreatic, lung, and breast cancer models and synergized with immune checkpoint inhibitors to enhance survival. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment characterized by selective reduction of myeloid-derived suppressor cells (MDSC) while increasing tumor infiltration of CD8+ T cells and natural killer cells. Moreover, ADT-030 augmented the efficacy of anti-PD1 antibody therapy in mice bearing CT26 tumors harboring the KRAS G12D mutation. Together, these results support IND-enabling studies of ADT-030 as monotherapy or combined with immunotherapy for a broad range of cancers. Citation Format: Gary A. Piazza, Xi Chen, Dhana Sekhar Reddy. Bandi, Ganji Purnachandra. Nagaraju, Kristy L. Berry, Sindhu Ramesh, Khalda Fadlalla, Md Yeashin. Gazi, Upender Manne, Jeremy B. Foote, Adam B. Keeton, Yulia Y. Maxuitenko, Donald J. Buchsbaum, Gong Zhou, Bassel F. El-Rayes. A novel PDE10 inhibitor that blocks RAS and β-catenin signaling and enhances tumor immunogenicity with robust activity to inhibit tumor growth and metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B036.