CDK6 Degradation Is Counteracted by p16(INK4A) and p18(INK4C) in AML

Simple Summary CDK4/6 kinase inhibitors show promising results in various subtypes of AML, which has been primarily assigned to the inhibition of CDK6. To bypass therapeutic resistances and tackle the kinase-dependent, as well as kinase-independent, functions of CDK6, new CDK6 degraders have been developed. Here, we present insights into the mechanistic requirements for the efficacy of a CDK6-specific degrader in AML. We show that the presence and levels of the INK4 proteins p16(INK4A) and p18(INK4C) determine the extent of CDK6 degradation. Our study reveals the importance of INK4 protein levels as predictive markers for CDK6-targeted therapy in AML. Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option. We show that the efficacy of the CDK6-specific protein degrader BSJ-03-123 varies among AML subtypes and depends on the low expression of the INK4 proteins p16(INK4A) and p18(INK4C). INK4 protein levels are significantly elevated in KMT2A-MLLT3+ cells compared to RUNX1-RUNX1T1+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16(INK4A) or p18(INK4C) are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive markers for CDK6 degradation-targeted therapies in AML.