2. Academic Validation
  3. PRMT inhibition induces a viral mimicry response in triple-negative breast cancer

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

  • Nat Chem Biol. 2022 Aug;18(8):821-830. doi: 10.1038/s41589-022-01024-4.
Qin Wu  # 1,  David Y Nie  # 2 3 4,  Wail Ba-Alawi 3 4,  YiShuai Ji 5 6,  ZiWen Zhang 5,  Jennifer Cruickshank 4,  Jillian Haight 4,  Felipe E Ciamponi 7,  Jocelyn Chen 3 4,  Shili Duan 4,  Yudao Shen 8,  Jing Liu 8,  Sajid A Marhon 4,  Parinaz Mehdipour 4 9,  Magdalena M Szewczyk 2,  Nergiz Dogan-Artun 4,  WenJun Chen 2,  Lan Xin Zhang 2,  Genevieve Deblois 10 11,  Panagiotis Prinos 2,  Katlin B Massirer 7,  Dalia Barsyte-Lovejoy 2 12,  Jian Jin 8,  Daniel D De Carvalho 3 4,  Benjamin Haibe-Kains 3 4 13 14 15,  XiaoJia Wang 5,  David W Cescon 4,  Mathieu Lupien 16 17 18,  Cheryl H Arrowsmith 19 20 21
Affiliations

Affiliations

  • 1 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 4 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 5 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
  • 6 School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
  • 7 Molecular Biology and Genetic Engineering Center (CBMEG), Medicinal Chemistry Center (CQMED), Structural Genomics Consortium (SGC-UNICAMP), University of Campinas-UNICAMP, Campinas, Brazil.
  • 8 Departments of Pharmacological Sciences and Oncological Sciences, Mount Sinai Center for Therapeutics Discovery, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 9 Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 10 Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal, Quebec, Canada.
  • 11 Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada.
  • 12 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 13 Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
  • 14 Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 15 Vector Institute, Toronto, Ontario, Canada.
  • 16 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 17 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [email protected].
  • 18 Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [email protected].
  • 19 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 20 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 21 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [email protected].
  • # Contributed equally.
PMID: 35578032 DOI: 10.1038/s41589-022-01024-4
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.

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