Cyclin-dependent kinase inhibitors for the treatment of lung cancer

ABSTRACT

Introduction

Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression in both normal and malignant cells, functioning through complex molecular interactions. Deregulation of CDK-dependent pathways is commonly found in both non-small cell and small cell lung cancer, and these derangements suggest vulnerabilities that can be exploited for clinical benefit.

Areas covered

In this review, the authors present an overview of the biology of CDKs in normal and malignant cells, with a focus on lung cancer, followed by an assessment of preclinical work that has demonstrated the vital role of CDKs in lung cancer development and progression, and the activity of CDK inhibitors in a variety of lung cancer models. Finally, the experience with clinical trials of CDK inhibitors in lung cancer is discussed along with the current status of these agents in cancer therapy.

Expert opinion

Despite strong biological rationale and promising preclinical studies, the results of clinical trials of CDK inhibitors in lung cancer have thus far been disappointing. Further clinical development of CDK inhibitors in lung cancer will depend on the identification of predictive biomarkers and the design of combination regimens that take advantage of the unique molecular alterations that drive lung cancer growth and survival.

KEYWORDS:

• Non-small cell lung cancer
• small cell lung cancer
• cyclin dependent kinase
• anticancer therapy

Article highlights

1. Cyclin dependent kinases (CDKs) are critical regulators of the cell cycle, acting in concert with a variety of molecular mediators at multiple points in the cell cycle to drive cellular proliferation.

2. Derangements in the expression and/or activation of cell cycle mediators, particularly within the CDK-cyclin-RB pathways, are commonly found in many cancers, including small cell and non-small cell lung cancer, and are integrally involved in malignant transformation and tumor progression.

3. Pharmacologic inhibition of CDK4 and CDK6 can inhibit cell growth and induce apoptosis in non-small cell lung cancer cell lines and preclinical models. Small cell lung cancer appears to be relatively resistant to CDK4/6 inhibition due to the near ubiquitous loss of RB activity.

4. Thus far, clinical trials of CDK4/6 inhibitors in patients with lung cancer have yielded disappointing results, even in study populations that have been selected based on rationale molecular biomarkers that should predict improved response.

5. The demonstration of clinical benefit for CDK inhibition in lung cancer will rely on the development of predictive biomarkers and biologically rational combination therapy. Such strategies might include: CDK4/6 inhibitors plus growth factor pathway inhibitors in patients with mutated signal transduction pathways; or CDK4/6 inhibitors plus immune checkpoint inhibitors in those with immunostimulated tumor phenotypes.

Declaration of Interest

G Kalemkerian has received research grants from Merck & Co., AbbVie and Takeda. The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

One referee is affiliated with, a science advisory board member (SAB) of and equity holder in Gatekeeper, Syros, Petra, C4, B2S and Soltego. Their lab also receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield and Sanofi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.