2. Academic Validation
  3. Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor

Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor

  • Sci Transl Med. 2021 Mar 31;13(587):eabg1168. doi: 10.1126/scitranslmed.abg1168.
Blandine Roux 1,  Camille Vaganay 1,  Jesse D Vargas 2,  Gabriela Alexe 3 4,  Chaima Benaksas 1,  Bryann Pardieu 1,  Nina Fenouille 1,  Jana M Ellegast 3 4,  Edyta Malolepsza 4,  Frank Ling 1,  Gaetano Sodaro 1,  Linda Ross 3 4,  Yana Pikman 3 4,  Amy S Conway 3 4,  Yangzhong Tang 2,  Tony Wu 2,  Daniel J Anderson 2,  Ronan Le Moigne 2,  Han-Jie Zhou 2,  Frédéric Luciano 5,  Christina R Hartigan 4,  Ilene Galinsky 6,  Daniel J DeAngelo 6,  Richard M Stone 6,  Patrick Auberger 7,  Monica Schenone 4,  Steven A Carr 4,  Josée Guirouilh-Barbat 8,  Bernard Lopez 8,  Mehdi Khaled 9,  Kasper Lage 4,  Olivier Hermine 10,  Michael T Hemann 11,  Alexandre Puissant 12,  Kimberly Stegmaier 13 4,  Lina Benajiba 12
Affiliations

Affiliations

  • 1 Université de Paris, INSERM U944 and CNRS UMR 7212, Institut de Recherche Saint Louis, Hôpital Saint Louis, APHP, 75010 Paris, France.
  • 2 Cleave Therapeutics Inc., San Francisco, CA 94105, USA.
  • 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 4 Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 5 IRCAN, INSERM U1081 and CNRS UMR 7284, 06189 Nice, France.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 7 C3M, INSERM U1065, Team Cell Death, Differentiation, Inflammation and Cancer, 06204 Nice, France.
  • 8 Université de Paris, INSERM U1016 and CNRS UMR 8104, Institut Cochin, 75014 Paris, France.
  • 9 INSERM U1186, Gustave-Roussy Cancer Center, Université Paris-Saclay, 94805 Villejuif, France.
  • 10 Université de Paris, INSERM U1163 and CNRS 8254, Institut Imagine, Hôpital Necker, APHP, 75015 Paris, France.
  • 11 Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 12 Université de Paris, INSERM U944 and CNRS UMR 7212, Institut de Recherche Saint Louis, Hôpital Saint Louis, APHP, 75010 Paris, France. lina.benajiba@inserm.fr kimberly_stegmaier@dfci.harvard.edu alexandre.puissant@inserm.fr.
  • 13 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. lina.benajiba@inserm.fr kimberly_stegmaier@dfci.harvard.edu alexandre.puissant@inserm.fr.
PMID: 33790022 DOI: 10.1126/scitranslmed.abg1168
Abstract

The development and survival of Cancer cells require adaptive mechanisms to stress. Such adaptations can confer intrinsic vulnerabilities, enabling the selective targeting of Cancer cells. Through a pooled in vivo short hairpin RNA (shRNA) screen, we identified the adenosine triphosphatase associated with diverse cellular activities (AAA-ATPase) valosin-containing protein (VCP) as a top stress-related vulnerability in acute myeloid leukemia (AML). We established that AML was the most responsive disease to chemical inhibition of VCP across a panel of 16 Cancer types. The sensitivity to VCP inhibition of human AML cell lines, primary patient samples, and syngeneic and xenograft mouse models of AML was validated using VCP-directed shRNAs, overexpression of a dominant-negative VCP mutant, and chemical inhibition. By combining mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ataxia telangiectasia mutated (ATM) kinase activation and subsequent DNA repair through homologous recombination in AML. A second-generation VCP inhibitor, CB-5339, was then developed and characterized. Efficacy and safety of CB-5339 were validated in multiple AML models, including syngeneic and patient-derived xenograft murine models. We further demonstrated that combining DNA-damaging agents, such as anthracyclines, with CB-5339 treatment synergizes to impair leukemic growth in an MLL-AF9-driven AML murine model. These studies support the clinical testing of CB-5339 as a single agent or in combination with standard-of-care DNA-damaging chemotherapy for the treatment of AML.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128724
    99.58%, p97 Inhibitor
    p97