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Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics.

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Targeting valosin-containing protein (VCP)/p97 may selectively kill cancer cells. This protein is crucial for protein degradation, and its inhibition can lead to cancer cell death.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Malignant cells exhibit increased basal protein synthesis, relying on unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways for survival.
  • Valosin-containing protein (VCP)/p97, an AAA+ ATPase, is essential for protein quality control and homeostasis by facilitating protein degradation via the ubiquitin-proteasome system (UPS).
  • p97 regulates ERAD, and its disruption causes protein accumulation, UPR activation, and proteotoxic cell death.

Purpose of the Study:

  • To review the molecular structure, cellular roles, and clinical potential of VCP/p97 as a cancer therapeutic target.
  • To focus on p97 inhibitors CB-5083 and CB-5339, the only ones in clinical trials.
  • To explore combination strategies to enhance therapeutic efficacy.

Main Methods:

  • Literature review of VCP/p97 function in cancer.
  • Analysis of existing clinical trial data for p97 inhibitors.
  • Discussion of molecular mechanisms and therapeutic strategies.

Main Results:

  • p97 inhibition selectively targets cancer cells with high protein synthesis rates.
  • CB-5083 and CB-5339 are clinical-stage p97 inhibitors.
  • Combination therapies show potential for improved outcomes.

Conclusions:

  • p97 is a promising precision target for cancer therapy.
  • Targeting p97 leverages the metabolic vulnerabilities of cancer cells.
  • Further research into combination strategies is warranted to maximize therapeutic benefits.