Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor PMID: 33790022

Target-related Cytokines

2026-09-23

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

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. [email protected] [email protected] [email protected].
13. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA 02215, USA. [email protected] [email protected] [email protected].

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.