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

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• 作者：Erik S. Knudsen¹ ; ² ; ^{eknudsen@email.arizona.edu} ; Agnieszka K. Witkiewicz¹ ; ² ; ³ ; ^{awitki@email.arizona.edu}
• 关键词：cell cycle ; cyclin D1 ; E2F ; RB ; breast cancer.
• 刊名：Trends in Cancer
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：3
• 期：1
• 页码：39-55
• 全文大小：2858 K
• 卷排序：3

文摘

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.