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Molecular Cancer Therapeutics
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Review

Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows

Patrick J. Roberts, Vishnu Kumarasamy, Agnieszka K. Witkiewicz and Erik S. Knudsen
Patrick J. Roberts
1G1 Therapeutics, Research Triangle Park, North Carolina.
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Vishnu Kumarasamy
2Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York.
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Agnieszka K. Witkiewicz
2Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York.
3Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York.
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Erik S. Knudsen
2Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York.
4Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
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  • ORCID record for Erik S. Knudsen
  • For correspondence: Erik.Knudsen@roswellpark.org
DOI: 10.1158/1535-7163.MCT-18-1161 Published August 2020
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Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the antitumor effects of cytotoxic chemotherapy in tumors that are CDK4/6 dependent. However, there are multiple preclinical studies that illustrate potent cooperation between CDK4/6i and chemotherapy. Furthermore, the combination of CDK4/6i and chemotherapy is being tested in clinical trials to both enhance antitumor efficacy and limit toxicity. Exploitation of the noncanonical effects of CDK4/6i could also provide an impetus for future studies in combination with chemotherapy. Thus, while seemingly mutually exclusive mechanisms are at play, the combination of CDK4/6 inhibition and chemotherapy could exemplify rational medicine.

Footnotes

  • Mol Cancer Ther 2020;19:1575–88

  • Received February 26, 2020.
  • Revision received April 17, 2020.
  • Accepted June 10, 2020.
  • Published first June 16, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (8)
August 2020
Volume 19, Issue 8
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Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows
Patrick J. Roberts, Vishnu Kumarasamy, Agnieszka K. Witkiewicz and Erik S. Knudsen
Mol Cancer Ther August 1 2020 (19) (8) 1575-1588; DOI: 10.1158/1535-7163.MCT-18-1161

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Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows
Patrick J. Roberts, Vishnu Kumarasamy, Agnieszka K. Witkiewicz and Erik S. Knudsen
Mol Cancer Ther August 1 2020 (19) (8) 1575-1588; DOI: 10.1158/1535-7163.MCT-18-1161
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  • Article
    • Abstract
    • CDK4/6 in Cell-cycle Progression
    • Pharmacologic Inhibitors of CDK4/6—Mechanisms of Action and Resistance
    • The Spectrum of CDK4/6i Tumor Sensitivities and Theoretical Intersection with Chemotherapy
    • CDK4/6-Independent Tumors—Host Protection
    • Antagonism of Chemotherapy-mediated Cytotoxicity in CDK4/6-dependent Preclinical Models
    • Potential Cooperation between CDK4/6i and Chemotherapy in Cancer Therapy in Preclinical Models
    • Strategies for Incorporating CDK4/6i into Chemotherapy Regimens
    • Summary and Underexplored Areas
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
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Molecular Cancer Therapeutics
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