Targeting CDK4 and CDK6 in hormone-dependent cancers.

FDA approval of selective CDK4/6 inhibitors (CDK4/6i) marked a groundbreaking development in cancer treatment. Decades of pre-clinical studies elucidated the route that certain cancer cells take to gain the cancer hallmark of uncontrolled proliferation, uncovering CDK4/6 as key players. Further investigation into the molecular underpinnings of this process revealed interconnected signaling between the CDK4/6 and estrogen receptor (ER) signaling axes, providing evidence that CDK4/6i would be particularly relevant in estrogen-driven cancers. Three FDA-approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, were independently developed and all exhibited efficacy against in vivo models of ER+ breast cancer. Clinical trials then confirmed the safety and efficacy of these drugs in patients. Ongoing clinical trials are now testing CDK4/6i in several other cancer models, including other hormone-driven cancers. Further mechanistic insights should reveal predictive biomarkers of response, and potential combination therapies to overcome resistance. This chapter provides an overview of the development of these drugs, their current utility, and their potential use in the treatment of multiple malignancies.