Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues

Abstract Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the developmen...

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Autores principales:	Paul B. Noto, Timothy W. Sikorski, Francesca Zappacosta, Craig D. Wagner, Rocio Montes de Oca, Matthew E. Szapacs, Roland S. Annan, Yan Liu, Charles F. McHugh, Helai P. Mohammad, Steven P. Piccoli, Caretha L. Creasy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/414cd6e4587d4953aac439af4a476cd3
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spelling	oai:doaj.org-article:414cd6e4587d4953aac439af4a476cd32021-12-02T12:42:19ZIdentification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues10.1038/s41598-020-78800-62045-2322https://doaj.org/article/414cd6e4587d4953aac439af4a476cd32020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78800-6https://doaj.org/toc/2045-2322Abstract Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at blocking the activity of protein arginine methyltransferases (PRMTs), which catalyze the formation of various methylated arginine products on a wide variety of cellular substrates. GSK3368715 is a small molecule inhibitor of type I PRMTs currently in clinical development. Here, we evaluate the effect of type I PRMT inhibition on arginine methylation in normal human peripheral blood mononuclear cells and utilize a broad proteomic approach to identify type I PRMT substrates. This work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) as a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.Paul B. NotoTimothy W. SikorskiFrancesca ZappacostaCraig D. WagnerRocio Montes de OcaMatthew E. SzapacsRoland S. AnnanYan LiuCharles F. McHughHelai P. MohammadSteven P. PiccoliCaretha L. CreasyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-19 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul B. Noto Timothy W. Sikorski Francesca Zappacosta Craig D. Wagner Rocio Montes de Oca Matthew E. Szapacs Roland S. Annan Yan Liu Charles F. McHugh Helai P. Mohammad Steven P. Piccoli Caretha L. Creasy Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
description	Abstract Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at blocking the activity of protein arginine methyltransferases (PRMTs), which catalyze the formation of various methylated arginine products on a wide variety of cellular substrates. GSK3368715 is a small molecule inhibitor of type I PRMTs currently in clinical development. Here, we evaluate the effect of type I PRMT inhibition on arginine methylation in normal human peripheral blood mononuclear cells and utilize a broad proteomic approach to identify type I PRMT substrates. This work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) as a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.
format	article
author	Paul B. Noto Timothy W. Sikorski Francesca Zappacosta Craig D. Wagner Rocio Montes de Oca Matthew E. Szapacs Roland S. Annan Yan Liu Charles F. McHugh Helai P. Mohammad Steven P. Piccoli Caretha L. Creasy
author_facet	Paul B. Noto Timothy W. Sikorski Francesca Zappacosta Craig D. Wagner Rocio Montes de Oca Matthew E. Szapacs Roland S. Annan Yan Liu Charles F. McHugh Helai P. Mohammad Steven P. Piccoli Caretha L. Creasy
author_sort	Paul B. Noto
title	Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
title_short	Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
title_full	Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
title_fullStr	Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
title_full_unstemmed	Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
title_sort	identification of hnrnp-a1 as a pharmacodynamic biomarker of type i prmt inhibition in blood and tumor tissues
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/414cd6e4587d4953aac439af4a476cd3
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Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues

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