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 post-menopausal ER-positive/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-CTLA4 antibodies.

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