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Ref Type

Journal Article

PMID

(30712867)

Authors

Yin C, Zhu B, Zhang T, Liu T, Chen S, Liu Y, Li X, Miao X, Li S, Mi X, Zhang J, Li L, Wei G, Xu ZX, Gao X, Huang C, Wei Z, Goding CR, Wang P, Deng X, Cui R

Title

Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell	176	5	2019 Feb 21	1113-1127.e16	Cell

URL

Abstract Text

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ZT-12-037-01	ZT-12-037-01	2	0

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ZT-12-037-01		EX-A3169		ZT-12-037-01 is an ATP-competitive small molecule inhibitor, which inhibits the kinase activity of STK19, potentially resulting in increased apoptosis and reduced tumor growth (PMID: 30712867).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
NRAS	S89A	missense	loss of function	NRAS S89A does not lie within any known functional domains of the Nras protein (UniProt.org). S89A demonstrates loss of both Nras phosphorylation and activation of downstream signaling as compared to wild-type Nras in cell culture (PMID: 30712867).
NRAS	S89D	missense	unknown	NRAS S89D does not lie within any known functional domains of the Nras protein (UniProt.org). S89D results in cell proliferation, colony formation and activation of Nras signaling similar to wild-type Nras in culture, but results in increased NRAS signaling and colony formation when combined with NRAS Q61R (PMID: 30712867), and therefore, its effect on Nras protein function is unknown.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61R	melanoma	sensitive	ZT-12-037-01	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ZT-12-037-01 treatment induced apoptosis and inhibited cell proliferation and colony formation in culture and reduced tumor growth and increased survival in cell line xenograft models of melanoma harboring NRAS Q61R (PMID: 30712867).	30712867
BRAF V600E	melanoma	decreased response	ZT-12-037-01	Preclinical - Cell culture	Actionable	In a preclinical study, melanoma cell lines harboring BRAF V600E demonstrated reduced inhibition of cell proliferation and induction of apoptosis compared to cells harboring NRAS Q61R in culture when treated with ZT-12-037-01 (PMID: 30712867).	30712867

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