The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies

Erik S. Knudsen, Agnieszka K. Witkiewicz

Research output: Contribution to journalReview articlepeer-review

160 Scopus citations


Inhibitors of cyclin-dependent kinases (CDKs) 4/6 have emerged as a powerful class of agents with clinical activity in several malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms of action of agents selectively targeting CDK4/6 have few parallels in the current pharmaceutical armamentarium against cancer. Notably, CDK4/6 inhibitors act downstream of most mitogenic signaling cascades, and this has implications for both clinical efficacy and resistance. Core knowledge of cell-cycle processes has provided insights into the mechanisms of intrinsic resistance to CDK4/6 inhibitors; however, the basis of acquired resistance versus durable response is only beginning to emerge. This review focuses on the mechanism of action of CDK4/6 inhibitors as well as on biomarkers to direct their precision use in rationally developed combination therapies.

Original languageEnglish (US)
Pages (from-to)39-55
Number of pages17
JournalTrends in Cancer
Issue number1
StatePublished - Jan 1 2017


  • E2F
  • RB
  • breast cancer.
  • cell cycle
  • cyclin D1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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