phaidra.vetmeduni.ac.at o:1891 DOI 10.3390/cancers14061554 CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C 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 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. eng Cell-Cycle; Inhibition; Program 2023-07-26T08:12:11.052Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Schmalzbauer;Belinda S.; FN:Belinda S. Schmalzbauer X-ORCID:https://orcid.org/0000-0002-1881-0883 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Karoline; FN:Karoline Kollmann X-ORCID:https://orcid.org/0000-0002-7937-4245 END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Fontaine;Frédéric; FN:Frédéric Fontaine END:VCARD BEGIN:VCARD VERSION:3.0 N:Mueller;André C.; FN:André C. Mueller END:VCARD BEGIN:VCARD VERSION:3.0 N:Zojer;Markus; FN:Markus Zojer END:VCARD BEGIN:VCARD VERSION:3.0 N:Nebenfuehr;Sofie; FN:Sofie Nebenfuehr END:VCARD BEGIN:VCARD VERSION:3.0 N:Knab;Vanessa M.; FN:Vanessa M. Knab X-ORCID:https://orcid.org/0000-0001-9493-7627 END:VCARD BEGIN:VCARD VERSION:3.0 N:Mayer;Isabella M.; FN:Isabella M. Mayer END:VCARD BEGIN:VCARD VERSION:3.0 N:Sperl;Clio-Melina; FN:Clio-Melina Sperl END:VCARD BEGIN:VCARD VERSION:3.0 N:Schirripa;Alessia; FN:Alessia Schirripa X-ORCID:https://orcid.org/0000-0001-5446-9136 END:VCARD BEGIN:VCARD VERSION:3.0 N:Thondanpallil;Teresemary; FN:Teresemary Thondanpallil END:VCARD BEGIN:VCARD VERSION:3.0 N:Heller;Gerwin; FN:Gerwin Heller X-ORCID:https://orcid.org/0000-0001-8742-5631 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 2081393 https://phaidra.vetmeduni.ac.at/o:1891 https://phaidra.vetmeduni.ac.at/api/object/o:1891/thumbnail LOMv1.0 discipline