Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models.

ABSTRACT: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for hormone receptor+ (HR+) breast cancer. However, their long-term efficacy is limited by acquired resistance, and CDK4/6i monotherapy remains ineffective in triple-negative breast cancer (TNBC). Here, we demonstrate that dual inhibition of CDK4/6 and CDK7 is a promising strategy to overcome therapeutic resistance in both HR+ and TNBC models. Kinetic analyses revealed that CDK7 inhibitors (CDK7i) primarily impair RNA polymerase II-mediated transcription rather than directly targeting cell cycle CDKs. This transcriptional suppression attenuated E2F-driven transcriptional amplification, a key mechanism for developing CDK4/6i resistance following the degradation of the retinoblastoma protein. Consequent

SUBMITTER: Kim S 

PROVIDER: S-EPMC12520673 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature