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CDK9 inhibitors reactivate p53 by downregulating iASPP

Jiale Wu1, Ying Liang1, Yun Tan1

  • 1State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200025, China.

Cellular Signalling
|December 24, 2019
PubMed

Insights

Researchers found that inhibiting iASPP, a p53 inhibitor, restores the tumor-suppressive function of p53. Cyclin-dependent kinase 9 (CDK9) inhibitors reduce iASPP levels, reactivating p53 and showing promise for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Loss of p53 tumor-suppressive function is a common event in human cancer development.
  • iASPP acts as a negative regulator of p53, silencing its activity.
  • Restoring wild-type p53 function is a key therapeutic goal in cancer treatment.

Purpose of the Study:

  • To investigate the pharmacological inhibition of iASPP to restore wild-type p53 tumor-suppressive function.
  • To identify agents that can reactivate p53 by targeting iASPP.
  • To explore combination therapies for enhanced p53 reactivation in cancer.

Main Methods:

  • Utilized iASPP knockdown in HCT116 colon cancer cells to assess p53 activity.
  • Screened a drug library using isogenic HCT116 cell models to identify inhibitors of iASPP.
  • Analyzed TCGA pan-cancer cohort data to correlate iASPP expression with patient survival.

Main Results:

  • iASPP knockdown promoted p53 transcriptional activity and induced p53-dependent cell death.
  • CDK9 inhibitors were identified to downregulate iASPP transcriptionally, preferentially affecting p53+/+ cells.
  • CDK9 inhibitors demonstrated synergistic effects with MDM2 inhibitors in killing cancer cells.
  • iASPP overexpression predicted poor survival in wild-type p53 patients, especially with concurrent MDM2 overexpression.

Conclusions:

  • CDK9 inhibitors serve as effective p53-reactivating agents by downregulating iASPP.
  • Concurrent inhibition of iASPP and MDM2 presents a promising therapeutic strategy for reactivating p53 in cancer treatment.
  • Targeting iASPP offers a novel approach to restore p53's tumor-suppressive functions in various cancers.
Keywords:
CDK9 inhibitorConcurrent inhibitionMDM2iASPPp53 reactivation

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