Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells.
Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells.
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DOI：
10.1371/journal.pone.0189007
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Tseng LM
中科院分区：
文献类型：
--
作者：
Liu CY;Lau KY;Hsu CC;Chen JL;Lee CH;Huang TT;Chen YT;Huang CT;Lin PH;Tseng LM
三阴性乳腺癌（TNBC）缺乏特异性的药物靶点，仍然具有挑战性。Palbociclib是一种细胞周期蛋白依赖性激酶4和6 （CDK4/6）抑制剂，已被批准用于转移性雌激素受体（ER）阳性和人低温生长因子2 （HER2）阴性乳腺癌。帕博西尼抑制细胞周期的性质表明其在TNBC细胞中的潜力。视网膜母细胞瘤（RB，一种已知的CDK4/6底物）通路失调在TNBC中经常发生，研究表明，在RB精通的TNBC模型中，药理CDK4/6抑制诱导了与阿霉素的协同细胞抑制作用。此外，最近的研究报道，抗雄激素治疗在雄激素受体（AR）阳性的TNBC细胞中显示出临床前疗效。在这里，我们研究了帕博西尼联合抗雄激素enzalutamide在TNBC细胞中的作用。使用MDA-MB-453、BT-549、MDA-MB-231和MDA-MB-468 TNBC细胞系进行体外研究。Western blot检测蛋白表达。MTT法检测细胞抑制作用。流式细胞术检测细胞周期和凋亡情况。帕博西尼对rb阳性TNBC细胞有抑制作用，恩杂鲁胺对ar阳性TNBC细胞有抑制作用。恩杂鲁胺治疗可增强帕博西利诱导的ar阳性/ rb精通TNBC细胞的细胞抑制作用。此外，palbociclib介导的ar阳性/RB精通TNBC细胞的G1阻滞通过RB敲除而减弱。我们的研究为选择可能从CDK4/6抑制剂与AR拮抗剂联合治疗获益的患者提供了临床前依据。
Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models. In addition, recent studies reported that anti-androgen therapy shows preclinical efficacy in androgen-receptor (AR)-positive TNBC cells. Here we examined the effect of palbociclib in combination with an anti-androgen enzalutamide in TNBC cells. MDA-MB-453, BT-549, MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Protein expressions were assessed by Western blot analysis. Cytostatic effect was examined by MTT assay. Cell cycle and apoptosis were examined by flow cytometry. Palbociclib showed inhibitory effect in RB-proficient TNBC cells, and enzalutamide inhibited cell viability in AR-positive TNBC cells. Enzalutamide treatment could enhance the palbociclib-induced cytostatic effect in AR-positive/RB-proficient TNBC cells. In addition, palbociclib-mediated G1 arrest in AR-positive/RB-proficient TNBC cells was attenuated by RB knockdown. Our study provided a preclinical rationale in selecting patients who might have therapeutic benefit from combining CDK4/6 inhibitors with AR antagonists.
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影响因子：
7.3
作者：
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Sawyers, Charles L.
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影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
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三阴性乳腺癌的多个分子亚型批判性地依赖于雄激素受体，并在体内对enzalutamide反应。
影响因子：
5.7
作者：
Barton VN;D'Amato NC;Gordon MA;Lind HT;Spoelstra NS;Babbs BL;Heinz RE;Elias A;Jedlicka P;Jacobsen BM;Richer JK
通讯作者：
Richer JK