PRMT inhibition induces a viral mimicry response in triple-negative breast cancer

Qin Wu, David Y. Nie, Wail Ba-alawi, Yi Shuai Ji, Zi Wen Zhang, Jennifer Cruickshank, Jillian Haight, Felipe E. Ciamponi, Jocelyn Chen, Shili Duan, Yudao Shen, Jing Liu, Sajid A. Marhon, Parinaz Mehdipour, Magdalena M. Szewczyk, Nergiz Dogan-Artun, Wen Jun Chen, Lan Xin Zhang, Genevieve Deblois, Panagiotis PrinosKatlin B. Massirer, Dalia Barsyte-Lovejoy, Jian Jin, Daniel D. De Carvalho, Benjamin Haibe-Kains, Xiao Jia Wang, David W. Cescon, Mathieu Lupien, Cheryl H. Arrowsmith

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)821-830
Number of pages10
JournalNature Chemical Biology
Volume18
Issue number8
DOIs
StatePublished - Aug 2022

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