Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure
Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure
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DOI：
10.1038/onc.2010.154
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发表时间：
2010-07-15
期刊：
影响因子：
8
通讯作者：
Knudsen, E. S.
中科院分区：
文献类型：
--
作者：
Dean, J. L.;Thangavel, C.;Knudsen, E. S.
癌症的一个标志是细胞周期机制的失调，最终促进异常增殖，从而促进肿瘤发生和疾病进展。特别是在乳腺癌中，细胞周期蛋白D1在疾病的发展中起着至关重要的作用。最近，开发了一种高度特异性的CDK 4/6活性抑制剂（PD-0332991），可能对乳腺癌治疗有效。为了探究PD-0332991在治疗乳腺癌中的效用，在一组乳腺癌细胞系上评价了治疗应答。这些分析表明，Rb的慢性丢失与向CDK 4/6非依赖性状态的演变以及最终对PD-0332991的耐药性特异性相关。然而，为了直接询问Rb的功能后果，在代表永生化乳腺上皮细胞和乳腺癌的多种亚型的模型中进行敲除实验。这些研究显示Rb在介导对CDK 4/6抑制的应答中具有高度特异性的作用，所述应答依赖于通过E2 F表现的转录抑制，以及减弱CDK 2活性的能力。对PD-03322991的获得性耐药性与CDK 2抑制剂的衰减特异性相关，表明CDK功能的冗余是治疗失败的决定因素。尽管存在这些警告，但在特定模型中，PD-0332991是一种特别有效的治疗，可诱导Rb依赖性细胞抑制。综合起来，这些发现表明，在指导CDK抑制剂在临床上的利用充分了解细胞周期调控途径的至关重要性。Oncogene（2010）29，4018-4032; doi：10.1038/onc.2010.154; 2010年5月17日在线发表
A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic. Oncogene (2010) 29, 4018-4032; doi:10.1038/onc.2010.154; published online 17 May 2010