Researchers identified a mechanism for CDK4/6 inhibitor resistance in ER-positive, HER2-negative metastatic breast cancer in which cytosolic EZH2 inactivates Rb. The study positions EZH2 as an actionable driver that can help explain why some tumors escape CDK4/6 pathway blockade even after initial response. The findings reinforce the broader resistance framework for cell-cycle targeted therapy and offer a concrete target for combination strategies to extend durability.