Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
Departments of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Mol Cancer Res. 2020 Aug;18(8):1176-1188. doi: 10.1158/1541-7786.MCR-19-1245. Epub 2020 May 27.
The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.
第二代抗雄激素疗法（ADT）治疗转移性去势抵抗性前列腺癌（mCRPC）的增加与更致命、侵袭性更强的前列腺癌（AVPC）肿瘤的发病率增加同时发生，这些肿瘤已经失去了对雄激素受体（AR）信号的依赖。这些 AR 非依赖性肿瘤也可能转分化为表达神经内分泌谱系标志物，并被称为神经内分泌前列腺癌（NEPC）。最近的证据表明，激酶信号可能是 NEPC 的一个重要驱动因素。为了确定 NEPC 中可靶向的激酶，我们对几种 AR 非依赖性和 AR 依赖性前列腺癌细胞系进行了全局磷酸化蛋白质组学比较，发现了多个改变的信号通路，包括 AR 非依赖性细胞系中 RET 激酶活性的富集。临床 NEPC 患者样本和 NEPC 患者来源的异种移植显示出上调的 RET 转录本和 RET 途径活性。在多种 NEPC 的小鼠和人类模型中，对 RET 激酶进行遗传敲低或药物抑制可显著降低肿瘤生长并降低细胞活力。我们的结果表明，针对高表达 RET 的 NEPC 肿瘤中的 RET 进行靶向治疗可能是一种有效的治疗选择。目前，对于侵袭性神经内分泌前列腺癌患者的治疗选择有限，而且没有一种是治愈性的。意义：确定异常表达的 RET 激酶作为多种 NEPC 模型中肿瘤生长的驱动因素，为在 AVPC 患者中测试 RET 抑制剂的临床应用提供了重要的依据。
