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

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

• Tipo de documento: Artigo Científico
• Fonte: Nature Chemical Biology; v. N/A, p. 22-pg., 2022-05-16.

Resumo

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. (AU)

• Processo FAPESP: 15/25134-5 - Implementação computacional das análises de CLIP-seq para determinação de mRNAs-alvo e sítios de ligação da proteína Caprin-1
• Beneficiário: Felipe Eduardo Ciamponi
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 20/02006-0 - Caracterização molecular e estrutural de proteínas de ligação a RNA como alvos terapêuticos em câncer e neurologia
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Processo FAPESP: 16/25521-1 - Análise computacional de alterações transcriptômicas induzidas por grânulos de stress em células humanas
• Beneficiário: Felipe Eduardo Ciamponi
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/50897-0 - INCT 2014: Centro de Química Medicinal de Acesso Aberto
• Beneficiário: Katlin Brauer Massirer
• Modalidade de apoio: Auxílio à Pesquisa - Temático