The evolution of cyclin dependent kinase inhibitors in the treatment of cancer.

The cell cycle cyclin-dependent kinases (CDKs) play a critical role in controlling the transition between cell cycle phases, as well as cellular transcription. Aberrant CDK activation is common in cancer, and deregulation of the cell cycle a key hallmark of cancer. Although CDK4/6 inhibitors are now a standard-of-care option for first- and second-line HR+/HER2- metastatic breast cancer, resistance inevitably limits their clinical benefit. Early pan-CDK inhibitors targeted the cell cycle and RNA polymerase II phosphorylation, but were complicated by toxicity, providing a rationale and need for the development of selective CDK inhibitors. In this review, we highlight selected recent literature to provide a narrative review summarizing the current CDK inhibitor therapeutic landscape. We detail the challenges associated with targeting CDKs for the treatment of breast and other cancers and review emerging biomarkers that may aid response prediction. We also discuss the risk-benefit ratio for CDK therapy and explore promising combination approaches. Although CDK inhibitors may stem the proliferation of cancer cells, resistance remains an issue, and currently there are limited biomarkers to predict response to therapy. Ongoing research investigating CDK inhibitors in cancer is of paramount importance to define appropriate and effective treatment regimens.