Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361102 Fujian, China.
Cell. 2019 Feb 21;176(5):1113-1127.e16. doi: 10.1016/j.cell.2019.01.002. Epub 2019 Jan 31.
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19 knockin leads to skin hyperpigmentation and promotes NRAS-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.
NRAS 中的激活突变占黑色素瘤的 20%-30%，但尽管经过几十年的研究，与 BRAF 形成鲜明对比的是，目前还没有有效的抗 NRAS 疗法。在这里，我们确定了一个以前未被表征的丝氨酸/苏氨酸激酶 STK19 是一种新型的 NRAS 激活剂。STK19 磷酸化 NRAS，增强其与下游效应物的结合，并促进致癌 NRAS 介导的黑素细胞恶性转化。STK19 中的一个反复出现的 D89N 取代，其改变在 25%的人类黑色素瘤中被鉴定出来，代表了一种获得功能的突变，它与 NRAS 更好地相互作用，增强黑素细胞转化。STK19 基因敲入导致皮肤色素沉着增加，并促进体内 NRAS 驱动的黑色素瘤发生。最后，我们开发了 ZT-12-037-01（1a）作为一种特异性的 STK19 靶向抑制剂，并表明它能有效阻断致癌 NRAS 驱动的黑素细胞恶性转化和黑色素瘤在体内外的生长。总之，我们的研究结果为携带 NRAS 突变的黑色素瘤提供了一种新的可行的治疗策略。
