Reference Detail

Ref Type

Journal Article

PMID

(32156748)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	13	2020 Jul 01	3408-3419	Clin Cancer Res

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Chelidonine	Chelidonine	3	0

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