Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition

ABSTRACT

Introduction

Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) have had clinical success in treating hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Notably, CDK4/6i have expanded to the neoadjuvant setting for early breast cancer and other cancer types and potently synergize with immunotherapy. Other CDKs, including CDK7, CDK9, and CDK12/13, mainly function in transcriptional processes as well as cell cycle regulation, RNA splicing, and DNA damage response. Inhibiting these CDKs aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer.

Areas covered

We reviewed the applications of CDK4/6i, CDK7i, CDK9i and CDK12/13i for various breast cancer subtypes and their potentials for combination with immunotherapy. A literature search of PubMed, Embase, and Web of Science was conducted in April 2022.

Expert opinion

The use of CDK4/6i represents a major milestone in breast cancer treatment. Moreover, transcription-related CDKs play critical roles in tumor development and are promising therapeutic targets for breast cancer. Some relevant clinical studies are underway. More specific and efficient CDKis will undoubtedly be developed and clinically tested. Characterization of their immune-priming effects will promote the development of combination therapies consisting of CDKi and immunotherapy.

KEYWORDS:

• Breast cancer
• CDK4/6
• CDK7
• CDK9
• CDK12/13
• immunotherapy

Article highlights

• CDK7, CDK9, and CDK12/13 participate in cell cycle regulation, all phases of transcription, RNA splicing, and DNA-damage response

• Inhibition of transcriptional CDK aids in suppressing tumors, reversing drug resistance, increasing drug sensitivity, and enhancing anti-tumor immunity in breast cancer

• The immune-priming effects of CDK inhibitors promote the development of a combination therapy consisting of immunotherapy and CDKi

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

One referee has received honoraria from Pfizer, Lilly, Novartis, Roche, MSD, and AZ with respect to CDK4/6i and ICI. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82072900) and the Preferred Foundation of Zhejiang Province Postdoctoral Research Projects (Grant No. ZJ2021136).