CDK4 and cancer: Moreover, recent studies have implicated dysfunction in ubiquitination-dependent degradation of cyclin D1 as a key mechanism underlying insensitivity towards CDK4/6 inhibitors (CDK4/6is) in treating certain types of cancers.14–16 Thus, innate insensitivity or acquired resistance to CDK4/6is constitutes a major hindrance in the clinical application of these drugs.