CDK4/6 Inhibition in Breast Cancer: Mechanisms of Response and Treatment Failure

The purpose of this review is to describe the role of D-type cyclins and cyclin-dependent kinases (CDKs) 4 and 6 in breast cancer and to discuss potential biomarkers for sensitivity or resistance to CDK4/6 inhibitors. A small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitor response and resistance in breast cancer. Putative markers of response include estrogen receptor positivity, luminal patterns of gene expression, high cyclin D1 levels, and low p16 levels. Possible resistance mechanisms include loss of Rb function, overexpression/amplification of cyclin E, and CDK6 amplification. Most of these remain speculative and have not been validated in clinical specimens. If early successes with CDK4/6 inhibitors are to be capitalized upon, it is critical that our understanding of CDK4/6 biology in breast cancer extends beyond its current rudimentary state. Only then, we will be able to develop rational therapeutic combinations that further enhance the efficacy of these agents.