Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present

Abstract

Introduction: Intensive efforts, over the last decade, have been made to inhibit the kinase activity of cyclins that act as mediators during cell-cycle progression. Activation of the cyclin D1 oncogene, often by amplification or rearrangement, is a major driver of multiple types of human tumors including breast and squamous cell cancers, B-cell lymphoma, myeloma and parathyroid adenoma.

Areas covered: In this review, the authors summarize the activity of cyclins and cyclin-dependent kinases in cell-cycle progression and transcription. They focus on cyclin D1/CDK4/CDK6, a central mediator in the transition from G1 to S phase. Furthermore, the authors discuss the first generation of pan-cyclin-dependent kinase inhibitors that failed to meet expectation and discuss, in detail, the second generation of highly specific cyclin D1/CDK4/CDK6 inhibitors that are proving to be more efficacious.

Expert opinion: The mechanism by which cyclin D1 drives tumorigenesis may be dependent on kinase and kinase-independent functions. Further evidence is necessary to delineate the roles of cyclin D1 in early pre-neoplastic lesions where its overexpression may promote genomic instability in a kinase-independent manner.

Keywords::

• cancer
• CDK inhibitors
• cyclin D1
• cyclin-dependent kinase

Acknowledgment

The department disclaims responsibility for any analysis, interpretations or conclusions.

Declaration of interest

RG Pestell was supported in part by NIH grants R01CA070896, R01CA075503, R01CA132115, R01CA086072, R01CA137494, the Kimmel Cancer Center NIH Cancer Center Core grant, P30CA56036, a generous grant from the Dr. Ralph and Marian C. Falk Medical Research Trust, a grant from the Breast Cancer Research Foundation and a grant from the Pennsylvania Department of Health. M Velasco-Velazquez has also been supported by PAPIIT-UNAM IN219613 and a grant from “Instituto Científico Pfizer, México”. C Aguirre-Alvarado is supported through a POSDOC-UNAM grant. RG Pestell holds (> $10,000) ownership interests in, and serves as, CSO/Founder of the biopharmaceutical companies ProstaGene, LLC and AAA Phoenix, Inc. He additionally holds ownership interests (value unknown) for several submitted patent applications.

Notes

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