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.

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.

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

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