AI Article Synopsis

  • Cancer cells adapt to stress, creating weaknesses that can be targeted; a study found that VCP, a stress-related protein, is particularly vulnerable in acute myeloid leukemia (AML).
  • The research showed that AML is the most sensitive cancer type to VCP inhibition, validated through various models and techniques.
  • A new VCP inhibitor, CB-5339, was developed and shown to effectively work with DNA-damaging drugs like anthracyclines, supporting its potential for clinical testing in AML treatment.

Article 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 -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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672851PMC
http://dx.doi.org/10.1126/scitranslmed.abg1168DOI Listing

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