Hematology-Oncology Division, Department of Medicine, and Cancer Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Cancer Res. 2018 Sep 15;78(18):5203-5215. doi: 10.1158/0008-5472.CAN-17-3615. Epub 2018 Jul 16.
Prostate cancer 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 PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer 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 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 , 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 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 prostate cancer 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. The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. .
前列腺癌对抑制雄激素受体 (AR) 活性的疗法（雄激素剥夺疗法，ADT）有反应，但总会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 是 PI3K 的下游激活物，与多种途径的调节以及包括前列腺癌在内的癌症的发生有关。然而，其确切的作用机制，尤其是其内源性底物，仍有待确定。在这里，我们证明 AR 通过与 BMX 基因结合直接抑制前列腺癌细胞中的 BMX 表达，并且 BMX 表达随后在 ADT 后迅速增加。BMX 通过磷酸化其激活环中的磷酸酪氨酸-酪氨酸 (pYY) 基序，正向调节多种受体酪氨酸激酶的活性，从而产生 pYpY，这是完全激酶活性所必需的，从而促进 CRPC 的发展。为了评估 BMX 的活性，我们生成了一种 BMX 底物特异性抗体（抗-pYpY），并发现其反应性与临床样本中的 BMX 表达相关，支持 pYY 作为底物。用伊布替尼（作为相关 Tec 激酶 BTK 的抑制剂开发）或另一种 BMX 抑制剂 BMX-IN-1 抑制 BMX 在前列腺癌异种移植模型中显著增强了去势的反应。这些数据表明，ADT 反应中 BMX 的增加有助于增强酪氨酸激酶信号转导和随后出现的 CRPC，并且靶向 AR 和 BMX 的联合治疗可能对一部分患者有效。雄激素负调控酪氨酸激酶 BMX，并通过 ADT 后增强多种受体酪氨酸激酶的磷酸化和激活，促进去势抵抗性前列腺癌的发生。
