High CDK6 Protects Cells from Fulvestrant-Mediated Apoptosis and is a Predictor of Resistance to Fulvestrant in Estrogen Receptor-Positive Metastatic Breast Cancer
High CDK6 Protects Cells from Fulvestrant-Mediated Apoptosis and is a Predictor of Resistance to Fulvestrant in Estrogen Receptor-Positive Metastatic Breast Cancer
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DOI：
10.1158/1078-0432.ccr-15-1984
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发表时间：
2016-11-15
影响因子：
11.5
通讯作者：
Ditzel, Henrik J.
中科院分区：
文献类型：
--
作者：
Alves, Carla L.;Elias, Daniel;Ditzel, Henrik J.
目的：雌激素受体阳性（ER+）乳腺癌对内分泌治疗的抵抗仍然是一个主要的临床问题。最近，CDK 4/6抑制剂palbociclib联合来曲唑或氟维司群获批用于治疗ER+晚期乳腺癌。然而，CDK 4/6在内分泌耐药中的作用及其作为内分泌治疗反应的预测生物标志物的潜力仍不明确。实验设计：我们通过基因敲除和Palbociclib治疗研究了氟维司群耐药细胞中CDK 6表达增加的具体作用，并评估了对细胞增殖、凋亡和激酶活性的影响。此外，我们评估了CDK 6的表达在转移性乳腺癌患者治疗或不与fulvestrant.Results的样本：我们发现在两个fulvestrant耐药细胞模型与敏感细胞的CDK 6的表达增加。CDK 6表达的减少损害了氟维司群耐药细胞的生长并诱导了细胞凋亡。Palbociclib治疗通过改变视网膜母细胞瘤蛋白磷酸化使氟维司群耐药细胞对氟维司群重新敏感。来自接受氟维司群治疗的两个独立乳腺癌患者队列的转移性样本中的高CDK 6水平（N = 45和46）与氟维司群治疗的较短无进展生存期（PFS）显著相关（P = 0.0006和0.018），而在接受其他一线或二线/三线内分泌治疗的患者中未观察到相关性结论：CDK 6表达上调可能是克服氟维司群对乳腺癌细胞生长抑制的重要机制。在转移性病灶中表现出高CDK 6表达的晚期ER+乳腺癌患者在氟维司群治疗后显示出较短的PFS，因此可能从其治疗方案中添加CDK 4/6抑制剂中获益。（C）2016年AACR。
Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole or fulvestrant was approved for treatment of ER+ advanced breast cancer. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined.Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis, and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant.Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models versus sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib resensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer patients treated with fulvestrant (N = 45 and 46) correlated significantly with shorter progression-free survival (PFS) on fulvestrant treatment (P = 0.0006 and 0.018), whereas no association was observed in patients receiving other first- or second-/third-line endocrine treatments (N = 68, P = 0.135 and 0.511, respectively).Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens. (C)2016 AACR.