2区 · 医学
ArticleOA
作者: Nebenfuehr, Sofie ; Sperl, Clio-Melina ; Knab, Vanessa M. ; Sexl, Veronika ; Mayer, Isabella M. ; Klampfl, Thorsten ; Schmalzbauer, Belinda S. ; Schirripa, Alessia ; Kollmann, Karoline ; Fontaine, Frédéric ; Heller, Gerwin ; Thondanpallil, Teresemary ; Mueller, André C. ; Zojer, Markus
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.
