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CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML

Belinda S Schmalzbauer1, Teresemary Thondanpallil1, Gerwin Heller2

  • 1Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.

Cancers
|March 25, 2022
PubMed

Insights

Cyclin-dependent kinase 6 (CDK6) degraders show variable efficacy in acute myeloid leukaemia (AML) subtypes. INK4 protein levels (p16INK4A, p18INK4C) predict response, acting as biomarkers for targeted therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinase 6 (CDK6) is a therapeutic target in acute myeloid leukaemia (AML).
  • CDK4/6 inhibitors face resistance; CDK4/6 degraders offer an alternative by eliminating kinase-dependent and -independent effects.
  • The efficacy of CDK6 degraders in AML subtypes requires further investigation.

Purpose of the Study:

  • To investigate the efficacy of the CDK6-specific protein degrader BSJ-03-123 in different AML subtypes.
  • To identify factors influencing the response to CDK6 degradation therapy in AML.
  • To establish INK4 proteins as predictive biomarkers for CDK6 degradation-targeted therapies.

Main Methods:

  • Assessed the efficacy of BSJ-03-123 across various AML subtypes.
  • Measured INK4 protein levels (p16INK4A, p18INK4C) in different AML subtypes.
  • Investigated the interaction between INK4 proteins and CDK6 complexes in response to BSJ-03-123.

Main Results:

  • BSJ-03-123 efficacy varied among AML subtypes, correlating with low INK4 protein expression.
  • INK4 protein levels were significantly higher in KMT2A-MLLT3+ AML cells than in RUNX1-RUNX1T1+ cells.
  • CDK6 complexes with p16INK4A or p18INK4C were protected from BSJ-mediated degradation, influencing the proliferative response.

Conclusions:

  • INK4 protein levels are critical determinants of CDK6 degrader efficacy in AML.
  • INK4 proteins serve as predictive biomarkers for response to CDK6 degradation therapies in AML.
  • Targeting CDK6 degradation offers a promising therapeutic strategy for specific AML subtypes based on INK4 expression.
Keywords:
AMLCDK6Cdkn2aCdkn2cINK4degraderp16p18

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