We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor.
- Authors
Roux, Blandine; Vaganay, Camille; Vargas, Jesse D.; Alexe, Gabriela; Benaksas, Chaima; Pardieu, Bryann; Fenouille, Nina; Ellegast, Jana M.; Malolepsza, Edyta; Ling, Frank; Sodaro, Gaetano; Ross, Linda; Pikman, Yana; Conway, Amy S.; Tang, Yangzhong; Wu, Tony; Anderson, Daniel J.; Le Moigne, Ronan; Zhou, Han-Jie; Luciano, Frédéric
- Abstract
Advancing AML treatment: Targeting oncogene mutations can effectively treat subsets of patients with cancer, but different approaches are needed. Roux et al. conducted an in vivo screen to target non-oncogenic pathways essential for tumor survival and identified valosin-containing protein (VCP) as a stress-related vulnerability important for DNA repair in acute myeloid leukemia (AML). The authors developed a second-generation VCP inhibitor, CB-5339, which effectively treated AML and prolonged survival in syngeneic and patient-derived xenograft mouse models when used alone or when combined with anthracycline and cytarabine. CB-5339 does not produce off-target effects on phosphodiesterase 6, unlike the first-generation compound, and therefore may be more likely to continue into clinical trials. 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.
- Subjects
ACUTE myeloid leukemia; DNA repair; ADENOSINE triphosphatase; DRUG efficacy; ATAXIA telangiectasia; NUCLEOPHOSMIN
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 587, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abg1168