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|Ref Type||Journal Article|
|Authors||Qian L, Chen K, Wang C, Chen Z, Meng Z, Wang P|
|Title||Targeting NRAS-Mutant Cancers with the Selective STK19 Kinase Inhibitor Chelidonine.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 Jul 01|
|Abstract Text||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 while exhibiting minimal toxicity.Chelidonine suppresses NRAS-mutant cancer cell growth and could have utility as a new treatment for such malignancies.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Chelidonine||Chelidonine is a naturally occurring plant alkaloid that has been show to possess anti-inflammatory properties (PMID: 29044876), and may results in inhibition of Nras, p38-p53, and PI3K signaling (PMID: 32156748, PMID: 22979935), potentially leading to inhibition of tumor growth and cancer cell killing (PMID: 26677104, PMID: 32156748).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|NRAS Q61R||melanoma||sensitive||Chelidonine||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Chelidonine treatment inhibited activation of Nras and downstream signaling pathways, reduced proliferation and colony formation, and induced apoptosis in melanoma cells harboring NRAS Q61R in culture, and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 32156748).||32156748|
|NRAS Q61K||melanoma||sensitive||Chelidonine||Preclinical - Cell culture||Actionable||In a preclinical study, Chelidonine treatment inhibited activation of Nras and downstream signaling pathways, reduced proliferation and colony formation, and induced apoptosis in melanoma cells harboring NRAS Q61K in culture (PMID: 32156748).||32156748|
|NRAS Q61L||melanoma||sensitive||Chelidonine||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Chelidonine treatment inhibited activation of Nras and downstream signaling pathways, reduced proliferation and colony formation, and induced apoptosis in melanoma cells harboring NRAS Q61L in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 32156748).||32156748|