# Disrupting CDK9 activity suppresses triple-negative breast cancer and is enhanced by EGFR Inhibition

## TL;DR

Disrupting CDK9 activity can suppress triple-negative breast cancer, and combining it with EGFR inhibition enhances treatment effectiveness, though it increases toxicity.

## Contribution

The study demonstrates that CDK9 inhibition, especially in combination with EGFR inhibition, is a promising therapeutic strategy for TNBC.

## Key findings

- CDK9 inhibition significantly impaired TNBC cell proliferation and induced apoptosis.
- Combining CDK9 and EGFR inhibitors synergistically reduced tumor growth in xenograft models.
- Transcriptomic analysis showed downregulation of oncogenic pathways like TGF-β and Wnt/β-catenin.

## Abstract

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. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype for which effective targeted therapies remain limited. Here, we aimed to define the therapeutic potential of novel CDK9 inhibitors in TNBC.

We explored the efficacy and mechanism of action of novel CDK9 inhibitors, alone or in combination with EGFR inhibitors, using TNBC cell lines and in vivo xenograft models.

Targeting CDK9 significantly impaired proliferation and induced apoptosis in multiple TNBC cell lines. Transcriptomic analyses revealed that CDK9 inhibitors induced downregulation of genes involved in transcription, cell cycle progression, and oncogenic signalling pathways, including TGF-β and Wnt/β-catenin signalling. Combined CDK9 and EGFR inhibition disrupted transcriptional programs, enhanced TNBC cell death in vitro, and acted synergistically to reduce tumour growth in PDX and Hs578T xenograft models, although this combination was also associated with increased toxicity.

Our results position CDK9 as a promising therapeutic target in TNBC, either alone or in combination with EGFR inhibition, provided that side effects associated with this combination treatment can be controlled.

The online version contains supplementary material available at 10.1007/s13402-025-01154-6.