Abstract 4391: A novel dual inhibitor of RAS and β-catenin signaling with advantages over mutant-specific KRAS inhibitors to escape resistance has robust antitumor efficacy and activates antitumor immunity

Aberrant activation of RAS signaling due to oncogenic RAS mutations, constitutive activation of receptor tyrosine kinases, or gene amplifications are key drivers/dependencies of most human cancers. Co-occurring mutations in the APC/β-catenin pathway that often occur in gastrointestinal and other cancers also play a crucial role in tumorigenesis and likely contribute to resistance to KRAS inhibitors. Phosphodiesterase 10A (PDE10) is overexpressed in certain cancers compared with normal tissues, while known inhibitors or gene silencing selectively inhibit proliferation and induce apoptosis of PDE10-expressing cancer cell lines. In contrast, normal cells lacking PDE10 were remarkedly insensitive. A novel orally bioavailable PDE10 inhibitor, ADT-030, was identified by screening a proprietary indene library followed by chemical optimization with delivery advantages over conventional PDE10 inhibitors. PDE10 inhibition by ADT-030 was confirmed with enzymatic assays using recombinant PDE10 and in cancer cells by cellular thermal stability assays, as well as the ability of ADT-030 to activate cGMP/PKG signaling at concentrations that inhibit and bind PDE10. ADT-030 blocked RAS-MAPK/AKT signaling and destabilized β-catenin, suppressing the transcription of genes essential for cancer cell proliferation and survival (e.g., MYC, Cyclin D, Survivin). Cancer cells resistant to KRASG12C and KRASG12D inhibitors retained complete sensitivity to ADT-007. Oral administration of ADT-030 strongly inhibited tumor growth at doses without discernable 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 orthotopic mouse models of lung cancer. ADT-030 also inhibited metastasis in the 4T1 orthotopic model of breast cancer and synergized with anti-PD1 in the CT26 mouse model of colon cancer to enhance survival. In addition, ADT-030 inhibited tumor formation in chemical-induced models of lung cancer and the MMTV/neu mouse model of breast cancer. Finally, deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment characterized by selective induction of apoptosis in myeloid-derived suppressor cells (MDSC) while increasing tumor infiltration of CD8+ T cells and natural killer cells. Together, these results support IND-enabling studies of ADT-030 as a monotherapy or in combination with immunotherapy for a broad range of KRAS-driven/dependent cancers. Citation Format: Gary A. Piazza, Dhana Sekhar Reddy Bandi, Ganji Purnachandra Nagaraju, Kristy L. Berry, Khalda Fadlalla, Md Yeashin Gazi, Upender Manne, Xi Chen, Jeremy B. Foote, Adam B. Keeton, Yulia Y. Maxuitenko, Donald B. Buchsbaum, Bassel F. El Rayes, Gang Zhou. A novel dual inhibitor of RAS and β-catenin signaling with advantages over mutant-specific KRAS inhibitors to escape resistance has robust antitumor efficacy and activates antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4391.