CDK4/6 Inhibitors Suppress RB-Null Triple-Negative Breast Cancer by Inhibiting Mutant P53 Expression via RBM38 RNA-Binding Protein

<i>Background:</i> 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. <i>Methods:</i> 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). <i>Results:</i> 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. <i>Conclusions:</i> Collectively, our findings suggest that mutant p53 could serve as a potential biomarker for the therapeutic efficacy of CDK4/6 inhibitors.