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Related Experiment Video

Updated: Jan 13, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38

Jin Zhang1, Kexin Wen1, Ken-Ichi Nakajima1

  • 1Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California, Davis, CA 95616, USA.

Cancers
|October 29, 2025
PubMed
Summary

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors suppress triple-negative breast cancer cell survival by reducing mutant p53 expression. Mutant p53 may serve as a predictive biomarker for CDK4/6 inhibitor therapy efficacy.

Keywords:
CDK4/6 inhibitorsRBRBM38 RNA binding proteinmRNA translationmutant p53

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are established treatments for hormone receptor-positive, HER2-negative breast cancer.
  • Varied efficacy of CDK4/6 inhibitors necessitates new biomarkers for predicting treatment response and resistance.

Purpose of the Study:

  • To investigate the effect of CDK4/6 inhibitors on RB-proficient and RB-deficient triple-negative breast cancer (TNBC) cells.
  • To determine if mutant p53 can serve as a therapeutic target or prognostic marker for CDK4/6 inhibitors in TNBC.

Main Methods:

  • Assessing CDK4/6 inhibitor effects on TNBC cell lines with varying RB expression.
  • Investigating the role of mutant p53 in TNBC response to CDK4/6 inhibitors.
  • Examining the mechanism of mutant p53 suppression by CDK4/6 inhibitors, focusing on RBM38 and mRNA translation.

Main Results:

  • CDK4/6 inhibitors were found to suppress mutant p53 expression in both RB-proficient and RB-deficient TNBC cells.
  • The suppression of mutant p53 by CDK4/6 inhibitors was directly linked to reduced TNBC cell survival.
  • Mechanistically, CDK4/6 inhibitors inhibit mutant p53 mRNA translation via the RNA-binding protein RBM38, which is phosphorylated by CDK4.

Conclusions:

  • Mutant p53 expression levels could potentially serve as a predictive biomarker for the therapeutic efficacy of CDK4/6 inhibitors.
  • Targeting mutant p53 represents a potential strategy in CDK4/6 inhibitor therapy for TNBC.