Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer [RNA-Seq]

Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation, and plays multiple roles in RNA splicing, DNA damage-response, cell cycle and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.