o:1891 CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML en 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 p16INK4A and p18INK4C. 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 p16INK4A or p18INK4C 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. Cell-Cycle; Inhibition; Program 1552099 10.3390/cancers14061554 2023-07-26T08:05:04.576Z 44 yes 46 Belinda S. Schmalzbauer University of Veterinary Medicine Vienna 0000-0002-1881-0883 Teresemary Thondanpallil University of Veterinary Medicine Vienna person Gerwin Heller Medical University of Vienna person 0000-0001-8742-5631 Alessia Schirripa University of Veterinary Medicine Vienna person 0000-0001-5446-9136 Clio-Melina Sperl University of Veterinary Medicine Vienna person Isabella M. Mayer University of Veterinary Medicine Vienna person Vanessa M. Knab University of Veterinary Medicine Vienna person 0000-0001-9493-7627 Sofie Nebenfuehr University of Veterinary Medicine Vienna person Markus Zojer University of Veterinary Medicine Vienna person André C. Mueller CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences person Frédéric Fontaine CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences person Thorsten Klampfl University of Veterinary Medicine Vienna person 0000-0002-6666-9773 Veronika Sexl University of Veterinary Medicine Vienna person 0000-0001-9363-0412 Karoline Kollmann University of Veterinary Medicine Vienna person 0000-0002-7937-4245 application/pdf 2081393 https://phaidra.vetmeduni.ac.at/o:1891 no yes 16 70 1552253 Cancers 16 14 6 MDPI 2022