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Schmalzbauer, Belinda S.; Thondanpallil, Teresemary; Heller, Gerwin; Schirripa, Alessia; Sperl, Clio-Melina; Mayer, Isabella M.; Knab, Vanessa M.; Nebenfuehr, Sofie; Zojer, Markus; Mueller, André C.; Fontaine, Frédéric; Klampfl, Thorsten; Sexl, Veronika; Kollmann, Karoline

CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML

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  • Media type: E-Article
  • Title: CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML
  • Contributor: Schmalzbauer, Belinda S.; Thondanpallil, Teresemary; Heller, Gerwin; Schirripa, Alessia; Sperl, Clio-Melina; Mayer, Isabella M.; Knab, Vanessa M.; Nebenfuehr, Sofie; Zojer, Markus; Mueller, André C.; Fontaine, Frédéric; Klampfl, Thorsten; Sexl, Veronika; Kollmann, Karoline
  • Published: MDPI AG, 2022
  • Published in: Cancers, 14 (2022) 6, Seite 1554
  • Language: English
  • DOI: 10.3390/cancers14061554
  • ISSN: 2072-6694
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access