Phosphodiesterase 10 (PDE10) was previously reported to be overexpressed in various cancers and essential for cancer cell proliferation and survival. Here, we studied a novel PDE10 inhibitor, ADT-030, and found it to potently and selectively inhibit KRAS mutant PDAC cell proliferation and clonogenicity by inducing G2/M arrest and apoptosis. ADT-030 also inhibited motility of PDAC cells in vitro . These effects were mediated by increased cAMP/cGMP levels and activation of PKA/PKG. The growth inhibitory activity of ADT-030 was associated with reduced β-catenin and RAS signaling. Notably, ADT-030 also inhibited the growth of KRAS G12D and KRAS G12C mutant PDAC cells resistant to allele-specific KRAS inhibitors. Oral administration of ADT-030 significantly suppressed tumor growth, reduced lung and liver metastasis, and increased survival without systemic toxicity in syngeneic and patient-derived xenograft (PDX) PDAC models. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single-cell RNA sequencing revealed remodeling of the tumor microenvironment by ADT-030 with a more favorable immune suppressive profile to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate for the treatment of KRAS-mutant PDAC capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.
Sarvesh et al. (Sat,) studied this question.