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Updated: Jul 18, 2025

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics
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PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies

Vishnu Kumarasamy1, Zhe Gao2, Bosheng Zhao2

  • 1Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.

British Journal of Cancer
|August 25, 2023
PubMed
Abstract

Insights

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) shows varied responses. Combining palbociclib with FN-POM overcomes resistance by targeting Cyclin E/CDK2, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition presents differential cellular responses in various tumor models due to cell cycle redundancy.
  • Investigating differential CDK requirements in cell lines can determine responses to targeted pharmacological agents.

Purpose of the Study:

  • To explore the differential requirements of CDKs in various cell lines as a determinant of response to pharmacological agents targeting these kinases.
  • To evaluate the efficacy of novel therapeutic strategies combining CDK4/6 inhibitors with agents targeting other cell cycle regulators.

Main Methods:

  • Utilized proteolysis-targeted chimeras (PROTACs) conjugated with palbociclib (Palbo-PROTAC) for simultaneous degradation of CDK4 and CDK6.
  • Synthesized FN-POM by conjugating pomalidomide with the multi-kinase inhibitor FN-1501.
  • Investigated the effects of FN-POM in combination with palbociclib using patient-derived pancreatic ductal adenocarcinoma (PDAC) organoids and patient-derived xenograft (PDX) models.

Main Results:

  • Palbo-PROTAC demonstrated heterogeneous effects on cell cycle progression across different tumor models, highlighting variable CDK4/6 dependencies.
  • Cyclin E overexpression was identified as a mechanism of resistance to palbociclib by uncoupling the cell cycle from CDK4/6.
  • Elevated P16INK4A expression antagonized PROTAC-mediated degradation of CDK4/6, while FN-POM effectively degraded Cyclin E and CDK2, inhibiting cell cycle progression in P16INK4A-high models.
  • The combination of palbociclib and FN-POM synergistically inhibited tumor cell proliferation through RB activation.

Conclusions:

  • Resistance to CDK4/6 inhibition can be overcome by pharmacologically targeting the Cyclin E/CDK2 complex.
  • This combination approach represents a potential therapeutic strategy for overcoming resistance to CDK4/6 inhibitors in cancer treatment.

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