https://phaidra.vetmeduni.ac.at/o:1891 CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML Schmalzbauer, Belinda S. Belinda S. Schmalzbauer 0000-0002-1881-0883 University of Veterinary Medicine Vienna Kollmann, Karoline Karoline Kollmann 0000-0002-7937-4245 University of Veterinary Medicine Vienna Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Fontaine, Frédéric Frédéric Fontaine CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences Mueller, André C. André C. Mueller CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences Zojer, Markus Markus Zojer University of Veterinary Medicine Vienna Nebenfuehr, Sofie Sofie Nebenfuehr University of Veterinary Medicine Vienna Knab, Vanessa M. Vanessa M. Knab 0000-0001-9493-7627 University of Veterinary Medicine Vienna Mayer, Isabella M. Isabella M. Mayer University of Veterinary Medicine Vienna Sperl, Clio-Melina Clio-Melina Sperl University of Veterinary Medicine Vienna Schirripa, Alessia Alessia Schirripa 0000-0001-5446-9136 University of Veterinary Medicine Vienna Thondanpallil, Teresemary Teresemary Thondanpallil University of Veterinary Medicine Vienna Heller, Gerwin Gerwin Heller 0000-0001-8742-5631 Medical University of Vienna MDPI text eng 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 http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:1891/download 10.3390/cancers14061554 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Cancers 14(6) (2022) Cancers 14 6 1.98 MB 2022