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

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

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...

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Hlavní autoři: Wu, Q, Nie, DY, Ba-Alawi, W, Ji, Y, Zhang, Z, Cruickshank, J, Haight, J, Ciamponi, FE, Chen, J, Duan, S, Shen, Y, Liu, J, Marhon, SA, Mehdipour, P, Szewczyk, MM, Dogan-Artun, N, Chen, W, Zhang, LX, Deblois, G, Prinos, P, Massirer, KB, Barsyte-Lovejoy, D, Jin, J, De Carvalho, DD, Haibe-Kains, B, Wang, X, Cescon, DW, Lupien, M, Arrowsmith, CH
Médium: Journal article
Jazyk:English
Vydáno: Springer Nature 2022
Témata:
RNA splicing
Chemical genetics
Cancer therapy
Screening
Popis
Shrnutí: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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