Disruption of transcriptional programming by CDK9 inhibition suppresses triple-negative breast cancer and is enhanced by EGFR inhibition

CDK9, in complex with cyclin T1 or T2, is essential for mRNA transcription by enabling paused RNA polymerase II to proceed into elongation. Increasing evidence highlights CDK9's involvement in transcriptional addiction in cancer. In this study, we explored the efficacy of novel CDK inhibitors and demonstrated that targeting CDK9 significantly impairs proliferation and induces apoptosis in various triple-negative breast cancer (TNBC) cell lines. Transcriptomic analysis revealed that CDK9 inhibition caused downregulation of genes governing transcription, cell cycle progression, and oncogenic signalling pathways, such as TGF-ß and Wnt/ß-catenin signalling. This disruption of transcriptional programs was further enhanced by combining CDK9 and EGFR inhibitors. Overall design: We performed RNA-sequencing to analyse the effects of 6 hours treatment with the CDK9 inhibitors I-73, Y3-21, D10-81 and combined CDK9 and EGFR inhibition by I-73 and lapatinib on gene expression in the Hs578T TNBC cell line.