Arrested Developments: CDK4/6 Inhibitor Resistance and Alterations in the Tumor Immune Microenvironment

The uncontrolled proliferation of cancer cells has led to the development of small-molecule inhibitors to target cell-cycle progression. Palbociclib, ribociclib, and abemaciclib are ATP-competitive inhibitors of cyclin-dependent kinases 4/6 (CDK4/6), which function early within the G₁ phase of the cell cycle. Recently, CDK4/6 inhibitors have gained FDA approval in postmenopausal estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer and testing in other cancer types is underway. However, resistance to CDK4/6 inhibitors frequently develops. In addition, targeting CDK4/6 may augment the action of immune checkpoint blockade agents. Here, we review recent studies that provide the preclinical rationale for treatment combinations and schedules that include CDK4/6 inhibitors. Furthermore, we discuss inhibitor effects on tumor-infiltrating lymphocytes as a preclinical rationale for targeting CDK4/6 in combination with anti-PD-1 or anti-CTLA-4 antibodies.