近日，来自美国的研究人员在国际学术期刊PNAS上发表了一项最新研究进展，他们在转移性前列腺癌细胞中发现了一些野生型蛋白激酶，可能在前列腺癌进展和转移过程中发挥了重要作用。这为前列腺癌干预治疗方法的开发提供了一些新的潜在靶点。
前列腺癌是威胁男性健康的一种恶性疾病，目前急需找到治疗转移性前列腺癌的治疗方法。众所周知，突变导致的蛋白激酶激活在许多癌症的进展和转移过程中发挥重要作用，但是虽然转移性前列腺癌中存在大量癌基因突变，蛋白激酶的突变却非常少。一些证据表明非突变型蛋白激酶及其相关信号途径可能参与前列腺癌进展，但是这些与前列腺癌转移存在机制关联性的激酶还没有得到深入了解。
在这项最新研究中，研究人员利用基于质谱技术的磷酸化蛋白质组学数据结合基因表达分析，选择了超过100种可能与人类转移性前列腺癌有关的蛋白激酶进行进一步功能分析。研究人员在小鼠前列腺癌细胞中对候选激酶进行过表达，通过这种方式进行初步的体内筛选，共发现20种能够促进癌转移的野生型激酶。
此后，研究人员又利用人类前列腺癌细胞对这20种激酶进行了第二轮体内筛选，结果发现RAF家族的三个成员，MERTK以及NTRK2都能够促进骨转移和内脏转移的形成，这一结果得到了PET-CT和组织学分析的证实。
研究人员指出，这些激酶都在人类转移性去势抵抗的前列腺癌组织中存在高表达。而这些功能研究表明特定野生型蛋白激酶在促进癌症转移方面具有强大作用，也提示这些激酶或可作为治疗干预的可能靶点得到进一步研究利用。
Functional screen identifies kinases driving prostate cancer visceral and bone metastasis
Claire M. Faltermeiera, Justin M. Drakeb,1, Peter M. Clarkb, Bryan A. Smithb, Yang Zongc, Carmen Volped, Colleen Mathisb, Colm Morrisseye, Brandon Castorf, Jiaoti Huangf,g,h,i,j, and Owen N. Witte
Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.