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
  • 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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