2. Academic Validation
  3. ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma

ADT-1004: a first-in-class, oral pan-RAS inhibitor with robust antitumor activity in preclinical models of pancreatic ductal adenocarcinoma

  • Mol Cancer. 2025 Mar 13;24(1):76. doi: 10.1186/s12943-025-02288-9.
Dhana Sekhar Reddy Bandi 1,  Ganji Purnachandra Nagaraju 1,  Sujith Sarvesh 1,  Julienne L Carstens 1,  Jeremy B Foote 2,  Emily C Graff 3,  Yu-Hua D Fang 4,  Adam B Keeton 5 6,  Xi Chen 5 6,  Jacob Valiyaveettil 5 6,  Kristy L Berry 5,  Sejong Bae 7,  Mehmet Akce 1,  Greg Gorman 8,  Karina J Yoon 9 10,  Upender Manne 11,  Michael R Boyd 6,  Donald J Buchsbaum 12,  Asfar S Azmi 13,  Yulia Y Maxuitenko 5,  Gary A Piazza 5 6,  Bassel F El-Rayes 14
Affiliations

Affiliations

  • 1 Department of Hematology and Oncology, O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama, Birmingham, AL, 35233, USA.
  • 2 Department of Microbiology, University of Alabama, Birmingham, AL, 35294, USA.
  • 3 Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, 36849, USA.
  • 4 Radiology and Neurology, University of Alabama, Birmingham, AL, 35233, USA.
  • 5 Drug Discovery and Development Department, Harrison College of Pharmacy, Auburn University, Auburn, AL, 36849, USA.
  • 6 ADT Pharmaceuticals, LLC, Orange Beach, AL, 31691, USA.
  • 7 Division of General Internal Medicine and Population Science, University of Alabama School of Medicine, Birmingham, AL, 35233, USA.
  • 8 Department of Pharmaceutical, Social and Administrative Sciences, Samford University, Birmingham, AL, 35229, USA.
  • 9 Department of Pharmacology and Toxicology, University of Alabama, Birmingham, AL, 35233, USA.
  • 10 Department of Cell, Developmental and Integrative Biology, University of Alabama, Birmingham, AL, 35294, USA.
  • 11 Department of Pathology, University of Alabama, Birmingham, AL, 35233, USA.
  • 12 Department of Obstetrics and Gynecology, University of Alabama, Birmingham, AL, 35233, USA.
  • 13 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
  • 14 Department of Hematology and Oncology, O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama, Birmingham, AL, 35233, USA. [email protected].
PMID: 40082968 DOI: 10.1186/s12943-025-02288-9
Abstract

Background: Oncogenic KRAS mutations occur in nearly, 90% of patients with pancreatic ductal adenocarcinoma (PDAC). Targeting KRAS has been complicated by mutational heterogeneity and rapid resistance. We developed a novel pan-RAS inhibitor, ADT-1004 (an oral prodrug of ADT-007) and evaluated antitumor activity in murine and human PDAC models.

Methodology: Murine PDAC cells with KRASG12D mutation (KPC-luc or 2838c3-luc) were orthotopically implanted into the pancreas of C57BL/6J mice, and four PDX PDAC tumors with KRAS mutations were implanted subcutaneously in NSG mice. To assess potential to overcome Ras Inhibitor resistance, parental and resistant MIA PaCa-2 PDAC cells (KRASG12C mutation) were implanted subcutaneously. Subcutaneously implanted RasWT BxPC-3 cells were used to assess the selectivity of ADT-1004.

Results: ADT-1004 potently blocked tumor growth and Ras activation in mouse PDAC models without discernable toxicity with target engagement and reduced activated Ras and ERK phosphorylation. In addition, ADT-1004 suppressed tumor growth in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Q mutations and increased CD4+ and CD8+ T cells in the TME consistent with exhaustion and increased MHCII+ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models resistant to these KRASG12C inhibitors and MRTX1133 resistant KRASG12D mutant cells. As evidence of selectivity for tumors with mutant KRAS, ADT-1004 did not impact the growth of tumors from RasWT PDAC cells.

Conclusion/significance: ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in Ras mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

Keywords

KRAS; Pancreatic ductal adenocarcinoma; RAS-driven malignancies; Tumor immune microenvironment; pan-RAS inhibitor.

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