BAF perturbation augments cancer cell dependence on CDK12-driven transcription elongation by RNA polymerase II

CDK12 facilitates transcriptional elongation and processivity by RNA polymerase II (Pol II). Although it has emerged as a promising player and target in cancer, better understanding of CDK12 gene transcription control could inform the design of novel anti-cancer strategies. Here, we define a co-dependency between CDK12 and BAF chromatin-remodeling complex in triple-negative breast cancer (TNBC). Using genome-scale CRISPR interference screening, we identify multiple BAF subunits as strong dependencies upon CDK12 inhibition. In turn, pharmacological co-targeting of CDK12 kinase and BAF ATPase activity synergizes in decreasing viability of multiple TNBC models. Mechanistically, the co-inhibition ablates di-phosphorylation of the Pol II C-terminal domain at Serine-2 and Serine-5 and drives Pol II accumulation on chromatin, upstream of apoptosis. Whereas inhibiting BAF primarily reduces transcription-coupled DNA accessibility, inhibiting CDK12 imposes a gene length-biased transcriptional defect that gets exacerbated by the co-inhibition. This lethal transcriptional imbalance is marked by synergistic induction of MYC and repression of long cell-cycle and mitotic genes. While MYC promotes apoptosis, co-inhibited cells show a failure in DNA synthesis and mitotic entry. Together, our findings define a regulatory axis in which impaired Pol II elongation heightens a requirement for BAF-dependent chromatin remodeling. This discovered co-dependency provides a rationale for co-targeting the CDK12-BAF axis in transcriptionally addicted cancers.