Prior to the advent of the monoclonal antibody trastuzumab, human epidermal growth-factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) was associated with an aggressive clinical course and poor survival outcomes. In the era of effective HER2-directed therapies, median survival rates for patients with metastatic HER2+ BC now approach 5 years. Despite these improvements, the majority of affected patients unfortunately die from disease. Therapies to overcome treatment resistance are being actively pursued. One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6), as they are downstream of HER2 and many of the cellular pathways driving resistance to HER2-targeted therapies, and play a key role in proliferation by controlling transition through the G1 restriction point to the S phase of the cell cycle. In this article, we review the published literature with regard to the rationale for CDK4/6-directed therapies in HER2+ BC and discuss ongoing clinical research and new challenges in the field.

中文翻译：

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CDK4 / 6i在HER2阳性乳腺癌中的新兴作用。

在单克隆抗体曲妥珠单抗问世之前，人类表皮生长因子受体2（HER2）阳性（HER2 +）乳腺癌（BC）与侵袭性临床病程和较差的生存结果相关。在有效的HER2指导治疗时代，转移性HER2 + BC患者的中位生存率现已接近5年。尽管有这些改进，不幸的是大多数受影响的患者死于疾病。正在积极地寻求克服治疗抗性的疗法。一种策略是靶向细胞周期蛋白依赖性激酶4/6（CDK4 / 6），因为它们位于HER2的下游，并且许多细胞途径驱动对HER2靶向疗法的耐药性，并通过控制过渡在增殖中起关键作用通过G1限制点到达细胞周期的S期。在本文中，