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ADT-030, a novel PDE10 inhibitor, demonstrates potent antitumor activity in pancreatic ductal adenocarcinoma

Dhana Sekhar Reddy BandiiD, Ganji Purnachandra NagarajuiD, Sujith SarveshiD, J. -W. Wang, Jeremy B. FooteiD, Adam B. KeetoniD, Xi CheniD, Verónica Ramírez‐AlcántaraiD, Thomas Holmes, Mehmet AkceiD, Anju SinghiD, Craig M. PowelliD, Santosh Kumar BeheraiD, Asfar Sohail AzmiiD, Elmar NurmemmedoviD, Ivan BabićiD, Gregory S. GormaniD, Lori Coward, Donald J. BuchsbaumiD, Yulia Y. MaxuitenkoiD, Gary Anthony PiazzaiD, Bassel F. El‐RayesiD

Abstract

Phosphodiesterase 10 (PDE10) has been noted to be highly expressed in multiple types of cancer and is crucial for the growth and maintenance of cancer cells found in colon, lung, and ovarian cancers. Here, we studied a novel orally bioavailable PDE10 inhibitor, ADT-030, and found that it potently inhibits the proliferation and clonogenicity of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cells at levels that block recombinant PDE10. ADT-030 also inhibited PDAC cell motility and triggered G2/M cell cycle halt and programmed cell death. These impacts were facilitated by raised cAMP/cGMP levels, activation of PKA/PKG, reduced {beta}-catenin and RAS signaling. Notably, ADT-030 diminished the proliferation of PDAC cells with KRASG12D and KRASG12C mutations that were resistant to both allele-specific and pan-RAS inhibitors. When administered orally, ADT-030 markedly decreased tumor growth, lowered the metastasis to the lungs and liver, and enhanced survival rates without causing systemic toxicity in both syngeneic and patient-derived xenograft (PDX) models of PDAC. 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 anti-tumor immune profile. The findings suggest that ADT-030 holds promise as a potential drug development candidate for treating KRAS-mutant PDAC by simultaneously targeting key oncogenic signaling pathways, resulting in tumor-intrinsic and immunomodulatory effects.

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Claude Opus 5.5 · xhigh effort · 7 Nov 2026 · from the full text of version 2 (3 Sept 2026) · CC BY 4.0

Oral PDE10 inhibitor ADT-030 curbed KRAS-mutant pancreatic cancer growth and metastasis in mouse models, stayed active in KRAS-inhibitor-resistant cells, and shifted tumor immune profiles.

The paper frames resistance to allele-specific and pan-RAS inhibitors as a main challenge in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), and notes that earlier PDE10 inhibitors were developed for CNS disorders while PDE10 work in cancer covered colon, lung and ovarian cells. It tests ADT-030, an orally dosed PDE10 inhibitor that reached high systemic levels in mice, in PDAC cell and mouse models.

Key results

  1. ShownADT-030 inhibits recombinant PDE10 and engages it in cells. It suppresses proliferation of KRAS G12D and G12C PDAC lines but barely affects the KRAS wild-type line BxPC-3. PDE10 knockdown made cells more sensitive to the drug.

    IC50 0.95 µM (cAMP) and 1.15 µM (cGMP) for recombinant PDE10; cellular binding EC50 0.9 µM; proliferation IC50 1.8-4.5 µM in mutant lines; BxPC-3 essentially insensitive. Enzyme assay n = 2 per concentration. · ADT-030 inhibition and binding of PDE10; ADT-030 inhibition in wild-type vs. mutant KRAS…; Figure legends

  2. ShownMechanistically, ADT-030 raises cAMP/cGMP and VASP phosphorylation (PKA/PKG activity), lowers non-phosphorylated β-catenin, pERK and pmTOR, and reduces GTP-bound RAS in KRAS-mutant lines but not in wild-type or KRAS-amplified lines.

    ELISA, Western blots and RAS-GTP pulldowns in 2838c3 (G12D) and MIA PaCa-2 (G12C) cells; RAS-GTP not reduced in BxPC-3, Panc 02, KLE and MKN1. Tumor Westerns showed lower pERK, pAKT and active β-catenin. Quantification is mostly by blot; replicate numbers are not given in the text. · ADT-030 inhibits PDE10 and activates PKA/PKG…; ADT-030 attenuates RAS and β-catenin signaling…; ADT-030 alters RAS and β-catenin signaling in…

  3. ShownIn orthotopic mouse models, oral ADT-030 shrank tumors dose-dependently, removed liver and lung metastases in the KPCML1 model, and added to gemcitabine plus nab-paclitaxel. The CNS-oriented PDE10 inhibitor PF-2545920 showed no antitumor effect and caused reduced mobility.

    Doses 50, 100 and 150 mg/kg for 23 days (n = 5 per group in the bioluminescence panels); regression in all mice at 150 mg/kg in the 2838c3 model; no body-weight effect. PF-2545920 IC50 25.02 and 24.1 µM vs 3.01 and 1.79 µM for ADT-030. Tolerance study: n = 5 vs 5, no notable blood or histology differences. · ADT-030 suppresses tumor growth in the…; ADT-030 inhibition of metastasis; ADT-030 enhances the antitumor efficacy of…; ADT-030 has increased potency and improved…

  4. ShownIn two PDX models (KRAS G12D and G12C) ADT-030 produced no tumor regrowth over 70 days after stopping treatment. It also inhibited proliferation of cells resistant to KRAS G12D, G12C and pan-RAS inhibitors.

    PDX: 150 mg/kg for 23 days, then 70 days follow-up while vehicle mice died. AsPC-1 parental IC50 1.75 µM vs MRTX1133-resistant 1.47 µM (MRTX1133: 43.74 nM vs >25 µM). RMC-6236- and BI-2865-resistant MIA PaCa-2 cells stayed sensitive to ADT-030. PDX group sizes are not stated. · ADT-030 suppresses tumor growth and induces…; ADT-030 suppresses the growth of KRASG12D and…; Discussion

  5. SuggestedFlow cytometry and scRNA-seq indicate immune remodeling: more infiltrating T, NK and dendritic cells, a higher M1/M2 macrophage ratio, and activated CD8 T and TNK states. Checkpoint-marker changes differed between the 2838c3 and KPC models.

    KPC scRNA-seq: higher CD69, Prf1, IFNγ and Gzma in CD8 T cells despite fewer total CD8 T cells; flow showed more CD8 T cells and lower PD-1, CTLA-4 and LAG-3 on them. In 2838c3 tumors the same checkpoint markers rose. IFN-γ ELISpot increased with treatment. · ADT-030 suppresses tumor growth in the…; ADT-030 enhances antigen-specific T cell…; ADT-030 promotes anti-tumor immunity in a mouse…; Single cell RNA-seq (scRNA-seq) of orthotopic…

Methods, data and reproducibility

Biochemical, cell and mouse experiments (orthotopic, metastasis, chemotherapy-combination and PDX models) characterize a PDE10 inhibitor in PDAC, supported by docking, flow cytometry and scRNA-seq of KPC tumors.

  • Public human PDAC scRNA-seq atlas (12 studies) mined for PDE10 expression; TCGA PDAC data for PDE10 vs KRAS · human · n = 229 patients · https://zenodo.org/records/14199536
  • scRNA-seq of orthotopic KPC tumors from vehicle and ADT-030 (150 mg/kg) treated mice · mouse · GSE327617
  • PDAC cell lines (PANC-1, AsPC-1, MIA PaCa-2, BxPC-3, 2838c3, KPC, KPCML1) including inhibitor-resistant derivatives · human and mouse
  • Orthotopic 2838c3, KPC and KPCML1 tumor models in C57BL/6J mice, dose-response and chemotherapy combination · mouse · n = 5 per group in bioluminescence panels
  • Two PDX models (KRAS G12D and G12C) in immunodeficient NOD scid Il2rg mice · human tumors in mouse
  • Tolerability study (blood counts, chemistry, histopathology) and pharmacokinetics · mouse · n = 5 vs 5 (tolerability); 4 per time point (pharmacokinetics)
Methods & tools
GLIDE docking, IMAP fluorescence polarization PDE assay, MTT assay, Annexin V/PI flow cytometry, RAS-GTP pulldown kit, Human Metabolic Pathways Array C2, Cell Ranger 9.0.1, Seurat 5.3.0, R 4.5.1, LC-MS/MS, ImageJ, GraphPad Prism
Code
https://github.com/sujithsrvsh/ADT030_scRNAseq
Data & accessions
https://zenodo.org/records/14199536
Reagents & environment
Cell Ranger 9.0.1; Seurat 5.3.0; R 4.5.1; aligned to mouse reference GRCm39.
Reproducibility gaps
Materials shared on request under an agreement; many protocols are cited to earlier publications; most replicate details and PDX group sizes are not given in the text.
Limitations (5)
  • The authors note that why ADT-030 inhibits RAS activation selectively in KRAS-mutant cells needs further study. · stated by the authors
  • The authors propose testing in genetically engineered mouse models and in combination with immune checkpoint blockade as future work. · stated by the authors
  • Long-term ADT-030 exposure led to PDE10 downregulation and metabolic rewiring in PANC-1 cells, which the authors describe as a possible adaptive resistance mechanism. · stated by the authors
  • Evidence is preclinical and mostly from mouse models and cell lines. PDX group sizes are not reported, and several numbers are described only qualitatively. Some details conflict (e.g., the PDE10-KRAS correlation is Pearson in the text and Spearman in the legend). · noted in this summary
  • Authors include patent assignees for ADT-030 and analogs, and the immune readouts are inconsistent across models (CD8 T cell counts and checkpoint markers differ between flow and scRNA-seq, and between 2838c3 and KPC). · noted in this summary

Who should read:Read this if you follow PDE10 or cyclic nucleotide signaling as a way around KRAS inhibitor resistance in pancreatic cancer and want the preclinical efficacy and immune scRNA-seq data.

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