Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.
Inhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer.
复制标题
DOI：
10.1038/s41467-021-25700-6
复制
发表时间：
2021-09-10
影响因子：
16.6
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Dang F;Nie L;Zhou J;Shimizu K;Chu C;Wu Z;Fassl A;Ke S;Wang Y;Zhang J;Zhang T;Tu Z;Inuzuka H;Sicinski P;Bass AJ;Wei W
尽管针对CDK4/6激酶的抑制剂(CDK4/6I)在治疗ER+/HER2-乳腺癌方面显示出良好的临床前景，但获得性耐药经常被观察到，需要机制知识来充分利用其临床潜力。在这里，我们报道了抑制CDK4/6促进了SP1TrCP1介导的泛素化和蛋白酶体的降解，并促进了β介导的CDK6转录激活。有趣的是，抑制CK1ε不仅有效地阻止了Rb1的降解，而且通过调节Sp1蛋白的稳定性来阻止CDK4/6I诱导的CDK6上调，从而在体外增强了CDK4/6I的疗效并克服了对CDK4/6I的耐药性。使用异种移植和PDX模型，我们进一步证明联合抑制CK1CDK4/6可以显著抑制体内肿瘤的生长。总之，这些结果揭示了CDK4/6I处理改变RB1和CDK6蛋白丰度从而驱动获得CDK4/6I抗性的分子机制。重要的是，我们发现CK1ε是增强CDK4/6抑制剂治疗效果的有效靶点。获得CDK4/6i耐药性是一个重大的临床挑战。在此，作者报道了抑制细胞角蛋白1ε可以阻止CDK4/6I耐药的获得，从而增强CDK4/6I在乳腺癌中的治疗效果。
Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors. Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.
登录
查看更多内容
影响因子：
8.8
作者：
Fukushima H;Ogura K;Wan L;Lu Y;Li V;Gao D;Liu P;Lau AW;Wu T;Kirschner MW;Inuzuka H;Wei W
通讯作者：
Wei W
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
50.3
作者：
Li, Zhiqiang;Razavi, Pedram;Chandarlapaty, Sarat
通讯作者：
Chandarlapaty, Sarat
影响因子：
50.5
作者：
Condorelli, R.;Spring, L.;Bardia, A.
通讯作者：
Bardia, A.
影响因子：
16.6
作者：
Formisano, Luigi;Lu, Yao;Arteaga, Carlos L.
通讯作者：
Arteaga, Carlos L.