Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Clin Cancer Res. 2020 Jul 1;26(13):3408-3419. doi: 10.1158/1078-0432.CCR-19-2604. Epub 2020 Mar 10.
Oncogenic mutations in NRAS promote tumorigenesis. Although novel anti-NRAS inhibitors are urgently needed for the treatment of cancer, the protein is generally considered "undruggable" and no effective therapies have yet reached the clinic. STK19 kinase was recently reported to be a novel activator of NRAS and a potential therapeutic target for NRAS-mutant melanomas. Here, we describe a new pharmacologic inhibitor of STK19 kinase for the treatment of NRAS-mutant cancers.
The STK19 kinase inhibitor was identified from a natural compound library using a luminescent phosphorylation assay as the primary screen followed by verification with an kinase assay and immunoblotting of treated cell extracts. The antitumor potency of chelidonine was investigated and using a panel of NRAS-mutant and NRAS wild-type cancer cells.
Chelidonine was identified as a potent and selective inhibitor of STK19 kinase activity. , chelidonine treatment inhibited NRAS signaling, leading to reduced cell proliferation and induction of apoptosis in a panel of NRAS-mutant cancer cell lines, including melanoma, liver, lung, and gastric cancer. , chelidonine suppressed the growth of NRAS-driven tumor cells in nude mice while exhibiting minimal toxicity.
Chelidonine suppresses NRAS-mutant cancer cell growth and could have utility as a new treatment for such malignancies.
NRAS 致癌突变可促进肿瘤发生。尽管新型抗 NRAS 抑制剂对于癌症治疗迫在眉睫，但由于该蛋白通常被认为“不可成药”，因此尚未有任何有效疗法进入临床。最近有研究报道，STK19 激酶是 NRAS 的一种新型激活剂，也是 NRAS 突变型黑色素瘤的潜在治疗靶点。本研究描述了一种新型 STK19 激酶抑制剂，用于治疗 NRAS 突变型癌症。
采用发光磷酸化测定法从天然化合物文库中鉴定出 STK19 激酶抑制剂，然后通过激酶测定法进行验证，并对经处理的细胞提取物进行免疫印迹分析，以确定其对 STK19 激酶的抑制活性。采用一组 NRAS 突变型和 NRAS 野生型癌症细胞，对千金藤素的抗肿瘤活性进行了研究。
千金藤素被鉴定为 STK19 激酶活性的有效且选择性抑制剂。千金藤素处理可抑制 NRAS 信号通路，导致一系列 NRAS 突变型癌细胞系（包括黑色素瘤、肝癌、肺癌和胃癌）的增殖减少和凋亡诱导。此外，千金藤素在裸鼠体内抑制了 NRAS 驱动的肿瘤细胞生长，同时表现出最小的毒性。
千金藤素可抑制 NRAS 突变型癌症细胞的生长，可作为治疗此类恶性肿瘤的新方法。
