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<p>Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR<sup>+</sup>) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting. Recent studies also suggest the use of CDK4/6-targeting agents in cancer immunotherapy. In this Review, we highlight recent advancements in the mechanistic understanding and development of pharmacological approaches targeting CDK4/6. Collectively, these developments pose new challenges and opportunities for rationally designing more effective treatments.</p>

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Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer

  • 期刊论文

  • 发表日期：

    2025年1月30日

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  • James J. Asciolla,
  • Xuewei Wu,
  • Christos Adamopoulos,
  • Evripidis Gavathiotis,
  • Poulikos I. Poulikakos

摘要

Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR+) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting. Recent studies also suggest the use of CDK4/6-targeting agents in cancer immunotherapy. In this Review, we highlight recent advancements in the mechanistic understanding and development of pharmacological approaches targeting CDK4/6. Collectively, these developments pose new challenges and opportunities for rationally designing more effective treatments.