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.
Abstract:
Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been developed and clinically used as a frontline targeted therapeutic agent for hormone receptor-positive (HR+), HER2-negative breast cancer. However, the efficacy for CDK4/6 inhibitors varies in different types of cancer and thus there is a need to identify new biomarkers that would help predict efficacy and/or resistance. Methods: We examined the effect of CDK4/6 inhibitors in both RB-proficient and -deficient triple-negative breast cancer (TNBC) cells. We also examined whether mutant p53 could be a target and/or prognostic marker for CDK4/6 inhibitors in (TNBC). Results: We found that CDK4/6 inhibitors suppress mutant p53 expression in both RB-proficient and RB-deficient TNBC cells. We also found that suppression of mutant p53 is responsible for CDK4/6 inhibitors suppressing TNBC cell survival. Mechanistically, we showed that CDK4/6 inhibitors suppress mutant p53 mRNA translation through the RNA-binding protein RBM38. Previously, we showed that when phosphorylated at serine 195, phosphorylated RBM38 interacts with eIF4G on p53 mRNA and promotes p53 mRNA translation. Indeed, we found that CDK4 phosphorylates RBM38 at serine 195, which subsequently enhances mutant p53 mRNA translation. Conclusions: Collectively, our findings suggest that mutant p53 could serve as a potential biomarker for the therapeutic efficacy of CDK4/6 inhibitors.
Insights
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.
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.
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