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

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 ATPase 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.

Voir la publication