TY - JOUR
T1 - PRMT inhibition induces a viral mimicry response in triple-negative breast cancer
AU - Wu, Qin
AU - Nie, David Y.
AU - Ba-alawi, Wail
AU - Ji, Yi Shuai
AU - Zhang, Zi Wen
AU - Cruickshank, Jennifer
AU - Haight, Jillian
AU - Ciamponi, Felipe E.
AU - Chen, Jocelyn
AU - Duan, Shili
AU - Shen, Yudao
AU - Liu, Jing
AU - Marhon, Sajid A.
AU - Mehdipour, Parinaz
AU - Szewczyk, Magdalena M.
AU - Dogan-Artun, Nergiz
AU - Chen, Wen Jun
AU - Zhang, Lan Xin
AU - Deblois, Genevieve
AU - Prinos, Panagiotis
AU - Massirer, Katlin B.
AU - Barsyte-Lovejoy, Dalia
AU - Jin, Jian
AU - De Carvalho, Daniel D.
AU - Haibe-Kains, Benjamin
AU - Wang, Xiao Jia
AU - Cescon, David W.
AU - Lupien, Mathieu
AU - Arrowsmith, Cheryl H.
N1 - Funding Information:
We thank the following organizations for supporting our study: the Terry Fox Research Institute (New Frontiers Research Program PPG-1064 to D.W.C., B.H.-K., M.L. and C.H.A.), the Canadian Institute for Health Research (CEEHRC team grant 158225 to M.L. and C.H.A., grant 363288 to B.H.-K., grant FDN154328 to C.H.A., grant 136963 to M.L. and fellowship award 430943 to Q.W.). This work was also supported by the Princess Margaret Cancer Foundation (M.L.), the Gattuso-Slaight Personalized Cancer Medicine Fund (B.H.-K.), National Natural Science Foundation of China (grant 82103287 to Q.W.), Zhejiang Provincial Natural Science Foundation (grant LR22B050001 to Q.W.), FAPESP (grants 2012/0195-3, 2014/50897-0 and 20/02006-0 to K.B.M. and fellowships 2016/25521-1 and 2015/25134-5 to F.E.C.), Ontario Institute for Cancer Research (Investigator Award to M.L.), Canadian Cancer Society (the Bernard and Francine Dorval Award for Excellence to M.L.) and the SGC. The SGC is a charity (register number 1097737) that received funding from AbbVie, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], Janssen, Merck KGaA (aka EMD in Canada and USA), Pfizer, Takeda and the Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU; EUbOPEN grant 875510) from the European Union and European Federation of Pharmaceutical Industries and Associations (EFPIA). We thank the Princess Margaret Living Biobank for organoid development and the Princess Margaret Bioinformatics group for assisting with the bioinformatic analysis. We acknowledge the use of instruments at the Shared Instrumentation Core Facility at the Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences.
Funding Information:
We thank the following organizations for supporting our study: the Terry Fox Research Institute (New Frontiers Research Program PPG-1064 to D.W.C., B.H.-K., M.L. and C.H.A.), the Canadian Institute for Health Research (CEEHRC team grant 158225 to M.L. and C.H.A., grant 363288 to B.H.-K., grant FDN154328 to C.H.A., grant 136963 to M.L. and fellowship award 430943 to Q.W.). This work was also supported by the Princess Margaret Cancer Foundation (M.L.), the Gattuso-Slaight Personalized Cancer Medicine Fund (B.H.-K.), National Natural Science Foundation of China (grant 82103287 to Q.W.), Zhejiang Provincial Natural Science Foundation (grant LR22B050001 to Q.W.), FAPESP (grants 2012/0195-3, 2014/50897-0 and 20/02006-0 to K.B.M. and fellowships 2016/25521-1 and 2015/25134-5 to F.E.C.), Ontario Institute for Cancer Research (Investigator Award to M.L.), Canadian Cancer Society (the Bernard and Francine Dorval Award for Excellence to M.L.) and the SGC. The SGC is a charity (register number 1097737) that received funding from AbbVie, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], Janssen, Merck KGaA (aka EMD in Canada and USA), Pfizer, Takeda and the Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU; EUbOPEN grant 875510) from the European Union and European Federation of Pharmaceutical Industries and Associations (EFPIA). We thank the Princess Margaret Living Biobank for organoid development and the Princess Margaret Bioinformatics group for assisting with the bioinformatic analysis. We acknowledge the use of instruments at the Shared Instrumentation Core Facility at the Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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. [Figure not available: see fulltext.].
AB - 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. [Figure not available: see fulltext.].
UR - http://www.scopus.com/inward/record.url?scp=85130132822&partnerID=8YFLogxK
U2 - 10.1038/s41589-022-01024-4
DO - 10.1038/s41589-022-01024-4
M3 - Article
C2 - 35578032
AN - SCOPUS:85130132822
VL - 18
SP - 821
EP - 830
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 8
ER -