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Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation
Blandine Roux1, Camille Vaganay1, Jesse D Vargas2
1Université de Paris, INSERM U944 and CNRS UMR 7212, Institut de Recherche Saint Louis, Hôpital Saint Louis, APHP, 75010 Paris, France.
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 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.
Insights
Valosin-containing protein (VCP) is a key vulnerability in acute myeloid leukemia (AML). Inhibiting VCP, particularly with the new drug CB-5339, shows promise for treating AML, alone or with chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cancer cells adapt to stress, creating vulnerabilities exploitable for targeted therapy.
- Acute myeloid leukemia (AML) cells exhibit stress-related vulnerabilities.
- Valosin-containing protein (VCP) is an AAA-ATPase implicated in cellular stress responses.
Purpose of the Study:
- To identify novel therapeutic targets in AML by screening for stress-related vulnerabilities.
- To investigate the role of VCP in AML pathogenesis and its potential as a therapeutic target.
- To evaluate the efficacy and safety of VCP inhibition, specifically with the novel inhibitor CB-5339, in AML models.
Main Methods:
- Pooled in vivo short hairpin RNA (shRNA) screening to identify VCP as a vulnerability in AML.
- Validation of VCP inhibition sensitivity using shRNAs, dominant-negative mutants, and chemical inhibitors in various AML models (cell lines, patient samples, murine models).
- Mass spectrometry-based interactome analysis and phospho-signaling studies to elucidate VCP's mechanism of action, focusing on ATM kinase activation and DNA repair.
Main Results:
- VCP was identified as a significant stress-related vulnerability in AML, with AML showing the highest responsiveness to VCP inhibition among 16 cancer types.
- VCP inhibition impairs AML growth by affecting ataxia telangiectasia mutated (ATM) kinase activation and homologous recombination DNA repair.
- The novel VCP inhibitor CB-5339 demonstrated efficacy and safety in preclinical AML models.
- Combination therapy of CB-5339 with DNA-damaging agents showed synergistic effects in reducing leukemic growth.
Conclusions:
- VCP is a critical mediator of stress adaptation and survival in AML.
- Targeting VCP with CB-5339 represents a promising therapeutic strategy for AML.
- CB-5339 warrants clinical investigation as a single agent or in combination with standard DNA-damaging chemotherapy for AML treatment.
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