Robust and durable antitumor activity of a novel PDE10 inhibitor, ADT-030, that enhances the efficacy of chemotherapy and immunotherapy by blocking RAS and beta-catenin signaling and overcoming resistance to RAS-selective inhibitors

Resistance to mutant or isoform-specific KRAS inhibitors from compensatory activation of MAPK/AKT signaling by unchecked non-mutant RAS isoforms supports the development of pan-RAS inhibitors. However, secondary mutations or aberrant activation of other oncogenic pathways (e.g., Wnt/APC/beta-catenin) may cause resistance to pan-RAS inhibitors. We and others have reported that the cyclic nucleotide-phosphodiesterase 10A (PDE10) isozyme is overexpressed in cancer cell lines and 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 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 also 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 beta-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 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. 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 clinical trials of ADT-030 as a monotherapy or in combination with chemotherapy or immunotherapy for a broad range of RAS-driven cancers.