Combined Androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib
Combined Androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib
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联合雄激素受体阻断克服了乳腺癌细胞对哌柏西利的耐药性
DOI：
10.7150/ijbs.30572
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Guan, Xiaoxiang
中科院分区：
文献类型：
--
作者：
Ji, Wenfei;Shi, Yaqin;Guan, Xiaoxiang
细胞周期蛋白D -细胞周期蛋白依赖性激酶4/6（CDK 4/6）-Rb轴的失调与乳腺癌进展有关，并且选择性CDK 4/6抑制剂在晚期乳腺癌中显示出有效活性，特别是在由雌激素受体（ER）驱动的肿瘤中。然而，对这些小分子抑制剂的耐药性已成为其首次使用后不可避免的临床问题。在这里，我们通过建立CDK 4/6抑制剂palbociclib耐药乳腺癌细胞系（MCF-7 pR）来研究耐药的潜在机制。在长时间暴露于palbociclib后，我们检测到ER信号转导丢失和雄激素受体（AR）增加。此外，我们证明了更多的本地化的AR在细胞核的MCF-7 pR相比，亲本细胞（MCF-7）。我们还报道了AR可以促进细胞周期的进展。阻断AR信号通路可降低G1-S期细胞周期蛋白的相对水平，消除Rb磷酸化，抑制S期转录程序的激活。此外，AR和CDK 4/6的双重抑制可在体外和体内逆转Palbociclib的耐药性。总之，我们的研究提供了证据表明，AR激活促进CDK 4/6抑制剂耐药的细胞周期进程和细胞增殖，并确定AR抑制作为一种公认的新的治疗策略，以治疗癌症中的CDK 4/6抑制剂耐药。
The dysregulation of cyclin D -Cyclin-dependent kinase 4/6 (CDK4/6)-Rb axis has been implicated in breast cancer progression and the selective CDK4/6 inhibitors have shown effective activity in advanced breast cancer, especially in tumors driven by the estrogen receptor (ER). However, resistance to these small molecular inhibitors has become an inevitable clinical issue after their initial use. Here, we investigated the potential mechanism of resistance by establishing a CDK4/6 inhibitor palbociclib-resistant breast cancer cell line (MCF-7pR). After prolonged exposure to palbociclib, we detected the loss of the ER signaling and an increase in androgen receptor (AR). Moreover, we demonstrated more localization of AR in the cell nucleus of MCF-7pR compared to the parental cell (MCF-7). We also reported that AR could promote the progression of the cell cycle. Blockade of AR signaling could reduce the level of the relative G1-S cyclins, abolish Rb phosphorylation and inhibit the activation of transcriptional programs in S phase. Furthermore, dual inhibition of AR and CDK4/6 could reverse the resistance of palbociclib both in vitro and in vivo. In sum, our studies provide evidence that AR activation promotes cell cycle progression and cell proliferation in CDK4/6 inhibitor resistance, and identify AR inhibition as a putative novel therapeutic strategy to treat CDK4/6 inhibitor resistance in cancer.