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Updated: Jun 18, 2025

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BAP1 loss confers sensitivity to bromodomain and extra-terminal inhibitors in renal cell carcinoma

Wen-Hui Shi1,2,3, Xiao-Lian Liu1,2, Run-Hua Zhou3

  • 1Clinical Pharmacy Center.

Anti-Cancer Drugs
|July 30, 2024
PubMed

Insights

Loss of the BAP1 tumor suppressor gene in renal cell carcinoma (RCC) increases sensitivity to BET inhibitors. This finding offers a promising targeted therapy for BAP1-mutated RCC, improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The tumor suppressor gene BAP1 is frequently mutated in renal cell carcinoma (RCC).
  • BAP1 loss-of-function mutations correlate with poor patient survival.
  • Targeted therapies for BAP1-mutated RCC are currently lacking.

Purpose of the Study:

  • To investigate the therapeutic potential of BET inhibitors in BAP1-mutated RCC.
  • To elucidate the mechanisms underlying BET inhibitor sensitivity in BAP1-deficient RCC.
  • To validate findings in immunocompetent murine models.

Main Methods:

  • Utilized ectopic and orthotopic allograft models in murine RCC cells with BAP1 deletion.
  • Assessed tumor growth and survival in immunocompetent murine models.
  • Investigated the impact of BAP1 loss on DNA repair capacity and response to BET inhibitors.

Main Results:

  • BAP1 loss enhances sensitivity to BET inhibitors in murine RCC models.
  • BAP1 deletion impairs DNA repair, increasing vulnerability to BET inhibitor-induced DNA damage.
  • Tumor growth in immunocompetent models is influenced by host-tumor microenvironment interactions, not solely BAP1 status.

Conclusions:

  • BET inhibitors demonstrate significant promise as a targeted therapy for BAP1-deficient RCC.
  • Immunocompetent animal models are crucial for evaluating anticancer therapies due to microenvironment interactions.
  • Understanding BAP1's role in DNA repair and microenvironment interactions is key for therapeutic development.

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