Phosphorylated RB represses the transcriptional activity of ETS1 to modulate the sensitivity of prostate cancer cells to CDK4/6 inhibitors [CUT&Tag]

CDK4/6 inhibitors are potential drugs for PCa treatment. Exploring underlying mechanism of cquired resistance to CDK4/6 inhibitors a is very important for the clinical application of these drugs. In the present study, we found that inhibiton of EGFR increased the sensitivity of PCa to CDK4/6 inhibitors in an RB-dependent manner. Mechanically, we demonstrate that the RB 249SPRT252 motif phosphorylated by CDK4/6 bound with ETS1 to transcriptionally decreased the expression of ZNF783, which inactivated the EGFR tyrosine kinase inhibitor resistance pathway. While, treatment with CDK4/6 inhibitors de-phosphorylated RB and diminished the interaction between RB and ETS1 to activated the EGFR tyrosine kinase inhibitor resistance pathway through enhancing the expression of ZNF783, which resulted in the acquired resistance of PCa to CDK4/6 inhibitors. Furthermore, we employed RB 249SPRT252 motif derived the phospho-mimic plasmid or PROTAC to verify the these findings. Collectively, this study not only revealed a new mechanism by which phosphorylated RB suppresses the transcriptionally function of ETS1 but also provided a novel strategy for enhancing the antitumor effect of CDK4/6 inhibitors on PCa.