GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327617/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327617GEOGSEfalseADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinomaPhosphodiesterase 10A (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 migration. 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 KRASG12D and KRASG12C 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) models. ADT-030 also increased chemotherapy response in orthotopic PDAC models. Immune phenotyping and single cell RNA revealed remodeling by ADT-030 with a more favorable immune suppressive tumor immune microenvironment to activate anti-tumor immunity. These results show that ADT-030 is a promising drug development candidate capable of simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects for the treatment of KRAS-mutant PDAC.2026/08/04GSE327617GSM9662271GSM966227019057327617Mus musculus