2. Academic Validation
  3. A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer

A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer

  • Cancer Res. 2025 Mar 3;85(5):956-972. doi: 10.1158/0008-5472.CAN-24-0323.
Jeremy B Foote 1,  Tyler E Mattox 2,  Adam B Keeton 3 4,  Xi Chen 3 4,  Forrest T Smith 3,  Kristy Berry 3,  Thomas W Holmes 3,  Junwei Wang 3,  Chung-Hui Huang 3,  Antonio Ward 2,  Amit K Mitra 3,  Veronica Ramirez-Alcantara 2,  Cherlene Hardy 1,  Karianne G Fleten 5 6,  Kjersti Flatmark 5 6,  Karina J Yoon 7,  Sujith Sarvesh 8,  Ganji P Nagaraju 8,  Dhana Sekhar Reddy Bandi 8,  Yulia Y Maxuitenko 3,  Jacob Valiyaveettil 2 4,  Julienne L Carstens 8,  Donald J Buchsbaum 9,  Jennifer Yang 10,  Gang Zhou 11,  Elmar Nurmemmedov 12,  Ivan Babic 12,  Vadim Gaponeko 13,  Hazem Abdelkarim 13,  Michael R Boyd 4,  Greg Gorman 14,  Upender Manne 15,  Sejong Bae 16,  Bassel F El-Rayes 8,  Gary A Piazza 3 4
Affiliations

Affiliations

  • 1 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 2 University of South Alabama, Mobile, Alabama.
  • 3 Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, Alabama.
  • 4 ADT Pharmaceuticals LLC, Orange Beach, Alabama.
  • 5 Department of Gastroenterological Surgery, Oslo University Hospital, The Radium Hospital, Oslo, Norway.
  • 6 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 7 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 8 Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 9 Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 10 University of Connecticut, Mansfield, Connecticut.
  • 11 Georgia Cancer Center, University of Augusta, Augusta, Georgia.
  • 12 CellarisBio LLC, San Diego, California.
  • 13 Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois.
  • 14 Department of Pharmaceutical, Social and Administrative Sciences, McWhorter School of Pharmacy, Samford University; Birmingham, Alabama.
  • 15 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 16 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
PMID: 39700396 DOI: 10.1158/0008-5472.CAN-24-0323
Abstract

Activated Ras is a common driver of Cancer that was considered undruggable for decades. Recent advances have enabled the development of Ras inhibitors, but the efficacy of these inhibitors remains limited by resistance. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide, that binds nucleotide-free Ras to block GTP activation of effector interactions and MAPK/Akt signaling, resulting in mitotic arrest and Apoptosis. ADT-007 potently inhibited the growth of RAS-mutant Cancer cells irrespective of the Ras mutation or isozyme. Wild-type Ras (RASWT) Cancer cells with GTP-activated Ras from upstream mutations were equally sensitive. Conversely, RASWT Cancer cells harboring downstream BRaf mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of Cancer cells to ADT-007 required activated Ras and dependence on Ras for proliferation, whereas insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS-mutant Cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immunocompetent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancers. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex Ras mutational landscape of many human cancers and to improve treatment of RAS-driven tumors. Significance: ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for Cancer cells with mutant Ras or activated Ras protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs.

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