Related Experiment Video

Updated: Oct 20, 2025

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
12:02

Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols

Published on: June 6, 2017

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Restoring order at the cell cycle border: Co-targeting CDK4/6 and CDK2

Rinath Jeselsohn1, Rachel Schiff2, Albert Grinshpun3

  • 1Breast Oncology Center, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Division of Molecular and Cellular Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA, USA.

Cancer Cell
|September 10, 2021
PubMed

Insights

Resistance to CDK4/6 inhibitors is a challenge. A new study identifies cyclin E-CDK2 and Myc signaling as key resistance pathways and introduces a novel CDK2/4/6 inhibitor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cyclin-dependent kinase (CDK) 4/6 inhibitors are crucial in cancer therapy.
  • Acquired resistance limits the long-term efficacy of CDK4/6 inhibitors.
  • Understanding resistance mechanisms is vital for developing next-generation therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving resistance to CDK4/6 inhibitors.
  • To identify novel therapeutic targets for overcoming treatment resistance.
  • To develop a new inhibitor targeting key resistance pathways.

Main Methods:

  • Utilized a CRISPR activation (CRISPRa) screen to identify genes conferring resistance.
  • Analyzed the role of identified pathways in CDK4/6 inhibitor resistance.
  • Developed and characterized a novel selective inhibitor of CDK2, CDK4, and CDK6.

Main Results:

  • Identified the cyclin E-CDK2 axis as a critical mediator of resistance.
  • Uncovered the involvement of Myc signaling in acquired resistance.
  • Developed PF-06873600, a potent and selective inhibitor targeting CDK2/4/6.

Conclusions:

  • The cyclin E-CDK2 axis and Myc signaling are key drivers of resistance to CDK4/6 inhibitors.
  • Targeting CDK2 in combination with CDK4/6 inhibition may overcome resistance.
  • PF-06873600 represents a promising therapeutic strategy for resistant cancers.

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