
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.21.595159
preprint
1
Article
Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment
Zhang Youyou
Xu Mu
Yuan Jiao
Hu Zhongyi
Jiang Junjie
Huang Jie
Wang Bingwei
Shen Jianfeng
Long Meixiao
Fan Yi
Montone Kathleen T.
Tanyi Janos L.
Tavana Omid
Chan Ho Man
Hu Xiaowen
Zhang Lin http://orcid.org/0000-0003-1998-0611

21 5 2024
2024.05.21.595159http://biorxiv.org/lookup/doi/10.1101/2024.05.21.595159
nihpp-2024.05.21.595159.pdf
Abstract

An “induced PARP inhibitor (PARPi) sensitivity by epigenetic modulation” strategy is being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARPi treatments. To expand its clinical applications and identify more efficient combinations, we performed a drug screen by combining PARPi with 74 well-characterized epigenetic modulators that target five major classes of epigenetic enzymes. Both type I PRMT inhibitor and PRMT5 inhibitor exhibit high combination and clinical priority scores in our screen. PRMT inhibition significantly enhances PARPi treatment-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMTs maintain the expression of genes associated with DNA damage repair and BRCAness and regulate intrinsic innate immune pathways in cancer cells. Analyzing large-scale genomic and functional profiles from TCGA and DepMap further confirms that PRMT1, PRMT4, and PRMT5 are potential therapeutic targets in oncology. Finally, PRMT1 and PRMT5 inhibition act synergistically to enhance PARPi sensitivity. Our studies provide a strong rationale for the clinical application of a combination of PRMT and PARP inhibitors in patients with HR-proficient ovarian or breast cancer.
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