BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer.
BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer.
复制标题
DOI：
10.1158/0008-5472.can-17-3615
复制
发表时间：
2018-09-15
期刊：
影响因子：
11.2
通讯作者：
Balk SP
中科院分区：
文献类型：
--
作者：
Chen S;Cai C;Sowalsky AG;Ye H;Ma F;Yuan X;Simon NI;Gray NS;Balk SP
前列腺癌（PCa）对抑制雄激素受体（AR）活性的治疗（雄激素剥夺治疗，ADT）有反应，但总是进展为去势抵抗性前列腺癌（CRPC）。Tec家族非受体酪氨酸激酶BMX在磷脂酰肌醇-3激酶的下游被激活，并参与多种途径的调节和包括PCa在内的癌症的发展。然而，其确切的作用机制，特别是其内源性底物，仍有待建立。在这里，我们表明，BMX表达PCa抑制AR通过结合BMX基因，BMX表达随后迅速增加，以响应ADT。在细胞系和异种移植模型中，BMX通过磷酸化激活环中的磷酸酪氨酸-酪氨酸（pYY）基序，产生完整激酶活性所需的pYpY，积极调节多种受体酪氨酸激酶（RTK）的活性，从而促进CRPC的发展。为了评估BMX在体内的活性，我们产生了BMX底物特异性抗体（抗pYpY），并发现其反应性与临床样品中的BMX表达相关，支持pYY作为体内底物。在PCa异种移植模型中，用伊曲替尼（开发为相关Tec激酶BTK的抑制剂）或另一种BMX抑制剂BMX-IN-1抑制BMX显著增强了对去势的反应。这些数据表明，ADT引起的BMX增加有助于增强酪氨酸激酶信号传导和随后出现CRPC，并且靶向AR和BMX的联合治疗可能在一部分患者中有效。
Prostate cancer (PCa) responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of phosphatidylinositol-3 kinase and has been implicated in regulation of multiple pathways and in the development of cancers including PCa. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here we demonstrate that BMX expression in PCa is suppressed directly by AR via binding to the BMX gene, and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases (RTK) through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate-specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a PCa xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.