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Updated: Aug 4, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance

Xueliang Gao1, Yongxia Wu2, Joel M Chick3

  • 1Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.

Cell Reports
|March 31, 2023
PubMed

Insights

High CDK6 expression in melanoma predicts poor immunotherapy response. Targeting cyclin D3/CDK6-activated PTPs in T cells, rather than CDK6 itself, can enhance anti-tumor immunity and overcome resistance.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immunotherapy resistance poses a significant challenge in cancer treatment.
  • High CDK6 expression in melanoma correlates with reduced patient survival during immunotherapy.

Purpose of the Study:

  • To investigate the role of CDK6 and its associated proteins in melanoma immunotherapy resistance.
  • To identify novel therapeutic targets for enhancing anti-tumor immune responses.

Main Methods:

  • Bioinformatic analysis of patient data.
  • In vitro cell depletion studies (CDK6, cyclin D3, CDK4, cyclin D1, D2).
  • Assessment of tumor immune microenvironment changes and T cell activation markers (CD3ζ phosphorylation).

Main Results:

  • CDK6 and cyclin D3, but not CDK4 or cyclins D1/D2, are crucial for tumor growth and immune evasion.
  • CDK6 depletion alters the tumor immune microenvironment, impacting CD8+ and CD4+ T cell anti-tumor activity.
  • CDK6 enhances PTP1B and TCPTP activity, suppressing T cell receptor signaling via CD3ζ dephosphorylation.
  • Inhibitors of PTP1B and TCPTP are more effective than CDK6 degraders in boosting T cell-mediated immunotherapy.

Conclusions:

  • Targeting CDK6-mediated regulation of PTP1B and TCPTP is a promising strategy to overcome immunotherapy resistance.
  • Inhibiting protein tyrosine phosphatases (PTPs) may enhance immunotherapy efficacy in resistant cancer patients.
Keywords:
CD3ζCDK6CP: CancerCP: ImmunologyPTP1BTCPTPcyclin D3

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