Targeting CDK4/6 in mantle cell lymphoma

Targeting the cell cycle represents a rational approach to mantle cell lymphoma (MCL) therapy, as aberrant expression of cyclin D1 and dysregulation of CDK4 underlie cell cycle progression and proliferation of MCL cells. Although cell cycle cancer therapy was historically ineffective due to a lack of selective and effective drugs, this landscape changed with the advent of selective and potent small-molecule oral CDK4/6 inhibitors. Here, we review the anti-tumor activities and clinical data of selective CDK4/6 inhibitors in MCL. We summarize the known mechanism of action of palbociclib, the most specific CDK4/6 inhibitor to date, and the strategy to leverage this specificity to reprogram MCL for a deeper and more durable clinical response to partner drugs. We also discuss integrative longitudinal functional genomics as a strategy to discover tumor-intrinsic genomic biomarkers and tumor-immune interactions that potentially contribute to the clinical response to palbociclib in combination therapy for MCL. Understanding the genomic basis for targeting CDK4/6 and the mechanisms of action and resistance in MCL may advance personalized therapy for MCL and shed light on drug resistance in other cancers.