Pharmacologic Inhibition of STK19 Impairs NRAS-Driven Melanoma

Oncogenic mutations in RAS proteins occur in 20% to 30% of all human tumors. Mutations in NRAS at Q61 occur primarily in melanoma and trap NRAS in a constitutively active conformation. Despite the development of effective therapies against mutant BRAF–driven melanoma, no selective inhibitors of NRAS have been identified. Yin, Zhu, Zhang, Liu, and colleagues screened a kinome-wide siRNA library and identified the kinase STK19 as a regulator of NRAS activity. Depletion of STK19 in human primary melanocytes reduced the activities of both wild-type and oncogenic NRAS; conversely, ectopic expression of STK19 restored NRAS signaling. Silencing of STK19 inhibited colony formation and proliferation of oncogenic NRAS-transformed melanocytes in vitro and impaired their tumor formation in vivo. STK19 preferentially phosphorylated GTP-loaded active NRAS at S89, which was important for oncogenic NRAS-driven proliferation in melanocytes, as mutation of this residue inhibited colony formation, proliferation, and tumor formation. Several human patients with melanoma harbored mutant STK19 (D89N), which bound and activated NRAS more efficiently than wild-type STK19, suggesting that enhanced NRAS signaling caused by STK19 gain-of-function mutations is a driving event in human melanoma. Consistent with this possibility, in oncogenic NRAS-knockin mice, STK19 D89N expression resulted in hyperpigmentation and accelerated initiation and incidence of melanoma. A small compound library screen yielded a competitive inhibitor of STK19, ZT-12-037-01 (1a). In vitro, 1a inhibited phosphorylation of NRAS in time- and dose-dependent manners. Treatment of melanocytes with 1a impaired colony formation, proliferation, and xenograft tumor formation by inhibiting STK19-induced NRAS signaling. Treatment with 1a inhibited phosphorylation of both wild-type and oncogenic NRAS but triggered apoptosis in cells harboring oncogenic NRAS only. These deleterious effects of 1a were specific to inhibition of STK19, as expression of 1a-resistant STK19 mutants rescued oncogenic NRAS signaling. Collectively, these results identify STK19 as a kinase critical to oncogenic NRAS signaling in melanoma and present a means to target this refractory subtype of melanoma.

Yin C, Zhu B, Zhang T, Liu T, Chen S, Liu Y, et al. Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis. Cell 2019 Jan 31 [Epub ahead of print].

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