CDK4 and breast cancer: CDK2 plays a main role in cell cycle checkpoint from G1 to S and aberrant CDK2 activation has been identified as a key resistance mechanism to CDK4/6 inhibition in HR+ breast cancer.11,13,14 Patients with CDK2 activation responded poorly to palbociclib.21 This underscores CDK2 as a promising strategy to mitigate resistance.14 Notably, effective targeting may require polypharmacology approaches, while CDK2 inhibition alone exhibits limited antitumor activity.18 co-inhibition of CDK2/4/6 could synergistically overcome resistance mechanisms.