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Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and

Pingzhao Zhang1,2, Dejie Wang3,4,5, Yu Zhao3

  • 1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

Nature Medicine
|August 15, 2017
PubMed

Insights

Speckle-type POZ protein (SPOP) mutations in prostate cancer impair the degradation of BET proteins, leading to resistance to BET inhibitors. Combination therapy with AKT inhibitors can overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Bromodomain and extraterminal domain (BET) protein inhibitors show promise as anticancer therapies.
  • Speckle-type POZ protein (SPOP) is frequently mutated in primary prostate cancer.
  • SPOP mutations can impact therapeutic efficacy.

Purpose of the Study:

  • To investigate the role of wild-type and mutant SPOP in the regulation of BET proteins.
  • To understand the mechanism of resistance to BET inhibitors in SPOP-mutant prostate cancer.
  • To identify potential therapeutic strategies for SPOP-mutant prostate cancer.

Main Methods:

  • In vitro binding assays to assess SPOP-BET protein interactions.
  • Ubiquitination and proteasomal degradation assays.
  • Analysis of SPOP mutations in prostate cancer cell lines and patient specimens.
  • Transcriptome and BRD4 cistrome analyses.
  • Combination therapy studies with AKT inhibitors.

Main Results:

  • Wild-type SPOP binds to and degrades BET proteins (BRD2, BRD3, BRD4) via ubiquitination.
  • Prostate cancer-associated SPOP mutants exhibit reduced binding to BET proteins, leading to their accumulation.
  • Accumulation of BET proteins in SPOP-mutant prostate cancer causes resistance to BET inhibitors.
  • SPOP mutations are associated with enhanced RAC1 and cholesterol biosynthesis gene expression and AKT-mTORC1 signaling activation.
  • Combination therapy with AKT inhibitors overcomes resistance to BET inhibitors in SPOP-mutant prostate cancer.

Conclusions:

  • SPOP mutations disrupt BET protein degradation, conferring resistance to BET inhibitors in prostate cancer.
  • SPOP mutations activate oncogenic signaling pathways, contributing to treatment resistance.
  • SPOP mutations can serve as biomarkers to guide BET inhibitor therapy.
  • Combination therapy with AKT inhibitors represents a promising strategy for SPOP-mutant prostate cancer.

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