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Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss
Open accessAbstract
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.
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Metadata
- Authors
- Fedoriw, A., Rajapurkar, S. R., O'Brien, S., Gerhart, S. V., Mitchell, L. H., Adams, N. D., Rioux, N., Lingaraj, T., Ribich, S. A., Pappalardi, M. B., Shah, N., Laraio, J., Liu, Y., Butticello, M., Carpenter, C. L., Creasy, C., Korenchuk, S., McCabe, M. T., McHugh, C. F., Nagarajan, R., Wagner, C., Zappacosta, F., Annan, R., Concha, N. O., Thomas, R. A., Hart, T. K., Smith, J. J., Copeland, R. A., Moyer, M. P., Campbell, J., Stickland, K., Mills, J., Jacques-O’Hagan, S., Allain, C., Johnston, D., Raimondi, A., Porter Scott, M., Waters, N., Swinger, K., Boriack-Sjodin, A., Riera, T., Shapiro, G., Chesworth, R., Prinjha, R. K., Kruger, R. G., Barbash, O., & Mohammad, H. P.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 36
- Issue
- 1
- Pages
- 100-114.e25
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2954328834
- Cited by
- 339
- References
- 48
- FWCI
- 9.31
- Type
- journal article
- Language
- en
- Open access
- bronze
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- CoChat. (2026). Citation check: Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss. https://app.cochat.ai/papers/10.1016/j.ccell.2019.05.014
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- Fedoriw, A., Rajapurkar, S. R., O'Brien, S., Gerhart, S. V., Mitchell, L. H., Adams, N. D., Rioux, N., Lingaraj, T., Ribich, S. A., Pappalardi, M. B., Shah, N., Laraio, J., Liu, Y., Butticello, M., Carpenter, C. L., Creasy, C., Korenchuk, S., McCabe, M. T., McHugh, C. F., . . . Mohammad, H. P. (2019). Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss. Cancer Cell. https://doi.org/10.1016/j.ccell.2019.05.014
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
