Targeting NRAS-Mutant Cancers with the Selective STK19 Kinase Inhibitor Chelidonine.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Ling QianPeng Wang

Abstract

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 in vitro kinase assay and immunoblotting of treated cell extracts. The antitumor potency of chelidonine was investigated in vitro and in vivo 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. In vitro, 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. In vivo, chelidonine suppressed the growth of NRAS-driven tumor cells in nude mice wh...Continue Reading

Citations

Aug 28, 2020·Frontiers in Molecular Biosciences·Irene VanniPaola Ghiorzo
May 29, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ya-Jia XieXing-Xing Fan
Jul 25, 2021·Journal of Hematology & Oncology·Kun ChenPeng Wang
Aug 28, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuan LiangJie Zhang

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