BIOBUSINESS BRIEFS

STK19: a new target for NRAS-driven cancer

Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. *These authors contributed equally.
Contact

Search for this author in:

Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Münster, Germany. *These authors contributed equally.
Contact

Search for this author in:

Oncogenic mutations in RAS GTPases occur in ~20–30% of human tumours. However, RAS proteins are highly challenging drug targets, and no selective direct inhibitors of NRAS have been reported. Serine/threonine-protein kinase 19 (STK19) has recently been identified as a regulator of NRAS activity (Cell 176, 1113–1127; 2019), and the development of STK19 inhibitors could be a novel intervention opportunity.

Biological functions

STK19 was first described more than two decades ago as a novel serine/threonine protein kinase that could phosphorylate α-casein and histones (J. Biol. Chem. 273, 30954–30960; 1998), but its characterization has been very limited until recently. In 2019, Yin and colleagues reported a kinome-wide siRNA screen that showed that knockdown of STK19 inhibited NRAS activity (Cell 176, 1113–1127; 2019). They found that mutant STK19 had an important role in driving melanomagenesis through activating downstream signalling by the most prevalent mutant form NRAS-Q61R, which is trapped in a constitutively active conformation (Front. Oncol. 24, 965; 2019). Furthermore, STK19 depletion decreased the amount of active NRAS, reducing downstream signalling and the proliferation and tumour-forming ability of melanocytes. The interaction between STK19 and NRAS was also investigated, and it was found that phosphorylation of an evolutionarily conserved Ser89 residue in NRAS by STK19 enhances the interaction between NRAS-Q61R and the effector proteins BRAF, CRAF and PI3Kα (Fig. 1a).

Fig. 1 | STK19 as an anticancer drug target. a | A simplified overview of the NRAS signalling pathway in melanoma. For details, see Front. Oncol. 24, 965; 2019 and Oncogene 32, 3009–3018; 2013. b | Structures and characteristics of two reported STK19 inhibitors.

STK19 is altered in around 25% of skin cutaneous melanoma cases. Analysis of the TCGA database revealed that an STK19-D89N mutation represents ~42% of the STK19 alterations, and it was found to be a gain-of-function mutation (Cell 176, 1113–1127; 2019). Interestingly, if the oncogenic NRAS-Q61R was also present, STK19-D89N further promoted human melanocyte proliferation and tumour formation. In mice, a sevenfold increase in melanoma incidence after 1 year was observed if both proteins are mutated compared with NRAS-Q61R alone.

Together, these findings indicate the potential of STK19 inhibition as a therapeutic strategy for NRAS-driven melanomas. Furthermore, the Ser89 residue in NRAS, which is phosphorylated by STK19, is conserved in other RAS family members, potentially increasing the range of cancers for which STK19 could be a promising target.

Chemical tools

Literature tool compounds for STK19 are sparse, mainly owing to its lack of inclusion in wider kinome screening panels. However, the recent paper by Yin and colleagues showed that the quinazoline-based kinase inhibitor ZT-12-037-01 (Fig. 1b) is a potent and highly selective inhibitor of STK19 (IC50 = 35 nM). ZT-12-037-01 shows dose-dependent inhibition of STK19 phosphorylation and inhibition of the growth of NRAS-Q61R mutant melanoma in mouse xenograft models (Cell 176, 1113–1127; 2019).

The natural product chelidonine (Fig. 1b) was also recently identified as an STK19 inhibitor (IC50 = 113 nM), with less selectivity than ZT-12-037-01 (Clin. Cancer Res. 10.1158/1078-0432.CCR-19-2604; 2020). Chelidonine inhibited NRAS-driven tumour growth in a mouse model.

These two inhibitors provide excellent starting points for further investigating STK19 biology and identifying potential drug candidates for RAS-driven cancers.

Nature Reviews Drug Discovery 19, 579 (2020)

Acknowledgements

This article is part of a series from the NIH Common Fund Illuminating the Druggable Genome (IDG) program. The goal of IDG is to catalyse research on understudied proteins from druggable gene families by providing reagents, phenotypes and a mineable database; focusing on GPCRs, kinases and ion channels. For more information, see https://druggablegenome.net/

Updates & Corrections

  • Update 21 July 2020: Further studies on STK19 have been reported very recently that are important to note in the context of this article, which discusses results from a 2019 paper by Yin et al. (Cell 176, 1113–1127; 2019). Rodríguez-Martínez et al. published a paper (Cell 181, 1295–1405; 2020) raising questions about the conclusions of the 2019 paper by Yin et al., including the annotation of STK19, the physiological relevance of a 41 kDa isoform of STK19 studied by Yin et al., whether STK19 is a canonical kinase and whether the D98N mutation is a melanoma driver. Yin et al. provided a response (Cell 181, 1406–1049; 2020), including follow-up experiments to confirm their original findings. Support for these original findings has also come from independent research by Qian et al. discussed in this article, which showed that STK19 is a kinase that binds ATP with NRAS as a substrate (Clin. Cancer Res. 26, 3408–3419; 2020). This was investigated with the aid of a narrow-spectrum kinase inhibitor, chelidonine, that was shown to directly inhibit STK19, as was the case with the compound ZT-12-037-01 reported by Yin et al. (Cell 176, 1113–1127; 2019). For both compounds, NRAS was used as substrate, and testing of direct ATP binding/phosphorylation as well as recording of DSF melt curves was performed, all of which support the rationale that STK19 is a kinase.

Competing Financial Interests

The authors declare no competing interests.

Nature Briefing

An essential round-up of science news, opinion and analysis, delivered to your inbox every weekday.