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

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 <i>in vitro</i> kinase assay and immunoblotting of treated cell extracts. The antitumor potency of chelidonine was investigated <i>in vitro</i> and <i>in vivo</i> 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. <i>In vitro</i>, 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. <i>In vivo</i>, 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.