Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer

Abstract

Background: Cyclin-dependent kinase (CDK) 7 is aberrantly overexpressed in many types of cancer and is an attractive target for cancer therapy due to its dual role in transcription and cell cycle progression. Moreover, CDK7 can directly modulate the activities of estrogen receptor (ER), which is a major driver in breast cancer. Breast cancer cells have exhibited high sensitivity to CDK7 inhibition in pre-clinical studies.

Methods: In this review, we provide a comprehensive summary of the latest insights into CDK7 biology and recent advancements in CDK7 inhibitor development for breast cancer treatment. We also discuss the current application of CDK7 inhibitors in different molecular types of breast cancer to provide potential strategies for the treatment of breast cancer.

Results: Significant progress has been made in the development of selective CDK7 inhibitors, which show efficacy in both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer (HR+). Moreover, combined with other agents, CDK7 inhibitors may provide synergistic effects for endocrine therapy and chemotherapy. Thus, high-quality studies for developing potent CDK7 inhibitors and investigating their applications in breast cancer therapy are rapidly emerging.

Conclusion: CDK7 inhibitors have emerged as a promising therapeutic strategy and have demonstrated significant anti-cancer activity in different subtypes of breast cancer, especially those that have been resistant to current therapies.

Fig. 1. CDK7 is a critical regulator of transcription.

Cell cycle progression is mediated through the phosphorylation of other CDKs (a). Phosphorylation of hormone receptors, Mediator and Pol II (b).

Fig. 2. CDK7 phosphorylates the CTD of RNA polymerase II (RNA Pol II) at serine 5 and serine 7 to regulate the initiation of transcription and promoter escape.

Yellow dots represent serine 2; red dots represent serine 5; and purple dots represent serine 7.

Fig. 3. As a component of the general transcription factor complex TFIIH, CDK7 regulates estrogen receptor (ER) activity.

Phosphorylation of Ser118 promotes ER activity.

Fig. 4. CDK7 activity is required for the expression of numerous genes involved in TNBC.

Tumour development is inhibited by a covalent CDK7 inhibitor.