Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer.

ABSTRACT: CDK4/6 inhibitors (CDK4/6i) with endocrine therapy are standard for hormone receptor-positive (HR⁺) metastatic breast cancer. However, most patients eventually develop resistance and discontinue treatment, and there is currently no consensus on effective second-line strategies. Here, we demonstrate that maintaining CDK4/6i therapy, either alone or in combination with CDK2 inhibitors (CDK2i), slows the growth of drug-resistant HR⁺ models by prolonging G1 progression. Mechanistically, sustained CDK4/6 blockade in drug-resistant cells reduces E2F transcription and delays G1/S via a non-canonical, post-translational regulation of retinoblastoma protein (Rb). Durable suppression of both CDK2 activity and growth of drug-resistant cells requires co-administration of CDK2i wi

SUBMITTER: Armand J 

PROVIDER: S-EPMC11601343 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature