CDK4/6 inhibitors arrest the cell cycle by activating Rb. But the authors provide compelling evidence that the story does not end there. A new Nature study shows that hypophosphorylated Rb unexpectedly enhances ER-mediated transcription. Rb relocates to enhancer regions and reactivates proliferative ER-target genes, including CCND1. So, paradoxically, CDK4/6 inhibition leads to: E2F ↓ → proliferation ↓ but at the same time Rb → ER transcription ↑ → proliferative counter-response ↑ Endocrine therapy shuts down this second pathway. This finding reveals a new mechanism that may help explain the strong biological rationale for combining CDK4/6 inhibition with endocrine therapy, while also pointing to a potential mechanism of resistance. nature.com/articles/s41586-0…