Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1.
Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1.
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DOI：
10.1038/s41388-022-02179-z
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Shokat KM
中科院分区：
文献类型：
--
作者：
Melnyk JE;Steri V;Nguyen HG;Hwang YC;Gordan JD;Hann B;Feng FY;Shokat KM
雄激素受体（AR）是侵袭性前列腺癌的核心驱动因素。在最初使用雄激素受体信号抑制剂（ARSi）治疗后，AR信号的再激活导致耐药性。AR mRNA的选择性剪接产生AR- v7剪接变体，这是目前ARSi耐药的不可药物机制：AR- v7缺乏配体结合结构域，激素和抗雄激素拮抗剂在其中起作用，但仍然激活AR信号传导。我们发现PKCβ是AR基因组位点的转录和剪接的可药物调节因子。我们确定了一种临床PKCβ抑制剂与fda批准的抗雄激素联合使用，作为抑制AR基因组位点表达的方法，包括AR- v7的表达，同时拮抗全长AR。PKCβ抑制可降低AR基因的总表达，从而降低AR- v7蛋白水平，并使前列腺癌细胞对当前的抗雄激素治疗敏感。我们证明这种组合可能是一种可行的治疗ar - v7阳性前列腺癌的策略。
The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.
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影响因子：
8.8
作者：
Bianchini, D.;Omlin, A.;Pezaro, C.;Lorente, D.;Ferraldeschi, R.;Mukherji, D.;Crespo, M.;Figueiredo, I.;Miranda, S.;Riisnaes, R.;Zivi, A.;Buchbinder, A.;Rathkopf, D. E.;Attard, G.;Scher, H. I.;de Bono, J.;Danila, D. C.
通讯作者：
Danila, D. C.
影响因子：
11.2
作者：
Graff, JR;McNulty, AM;Thornton, D
通讯作者：
Thornton, D
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
50.3
作者：
Cai C;He HH;Chen S;Coleman I;Wang H;Fang Z;Chen S;Nelson PS;Liu XS;Brown M;Balk SP
通讯作者：
Balk SP
影响因子：
11.2
作者：
Han, Dong;Chen, Sujun;Cai, Changmeng
通讯作者：
Cai, Changmeng