Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis

Journal article

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.

Authors: Yin, C; Zhu, B; Zhang, T; Goding, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell
• Volume: 176
• Issue: 5
• Pages: 1113-1127
• Publication date: 2019-01-31
• Acceptance date: 2019-01-02
• DOI: 10.1016/j.cell.2019.01.002
• EISSN: 1097-4172
• ISSN: 0092-8674
• Keywords: kinase inhibitor; melanomagenesis; drug screening; cancer; targeted cancer therapy; melanoma; STK19; NRAS; RAS