Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor
Blandine Roux, Camille Vaganay, Jesse D. Vargas, Gabriela Alexe, Chaı̈ma Benaksas, Bryann Pardieu, Nina Fenouille, Jana M. Ellegast, Edyta Małolepsza, Frank Ling, Gaetano Sodaro, Linda S. Ross, Yana Pikman, Amy Saur Conway, Yangzhong Tang, Tony T. Wu, Daniel J. Anderson, Ronan Le Moigne, Han-Jie Zhou, Frédéric Luciano, Christina R. Hartigan, Ilene Galinsky, Daniel J. DeAngelo, Richard M. Stone, Patrick Auberger, Monica Schenone, Steven A. Carr, Josée Guirouilh‐Barbat, Bernard S. López, Mehdi Khaled, Kasper Lage, Olivier Hermine, Michael T. Hemann, Alexandre Puissant, Kimberly Stegmaier, Lina Benajiba
Abstract
-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.