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Targeting AML dependency on VCP-mediated DNA repair through a selective second-generation small molecule inhibitor
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Edité par CCSD ; American Association for the Advancement of Science (AAAS) -
International audience. The development and survival of cancer cells require adaptive mechanisms to stress. Such adaptations confer intrinsic vulnerabilities, enabling the selective targeting of cancer cells. Through a pooled in vivo shRNA screen, we identified the AAA-ATPase 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 a mass spectrometry-based analysis of the VCP interactome and phospho-signaling studies, we determined that VCP is important for ATM kinase activation and subsequent DNA repair in AML. Finally, we report a second-generation, clinical candidate VCP inhibitor, CB-5339, and validate its efficacy in multiple AML models, providing data to support the clinical testing of single agent CB-5339 or its combination with standard of care AML DNA damaging chemotherapy.
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