PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition
Year: 2023
Type: article
Abstract: Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.
Source: Cell Reports Medicine
Authors: Yang Li, Lacey E. Dobrolecki, Christina Sallas, Xudong Zhang, Travis D. Kerr, Deepa Bisht, Yalong Wang, Sharad Awasthi, Babita Kaundal, Siqi Wu, Weiyi Peng, Marc L. Mendillo, Yiling Lu, Collene R. Jeter, Guang Peng, Jinsong Liu, Shannon N. Westin, Anil K. Sood, Michael T. Lewis, Jishnu Das, S. Stephen Yi, Mark T. Bedford, Daniel J. McGrail, Nidhi Sahni
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: American Cancer Society, GlaxoSmithKline, Merck, Cancer Prevention and Research Institute of Texas, Susan G. Komen, Andrew Sabin Family Foundation, Ovarian Cancer Research Fund Alliance, Ovarian Cancer Research Alliance, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences
Awards: G111615301, G1619438925, G1702654540, G2779272668, G3582685175, G4095781974, G4711722764, G4819239071, G5396351703, G5465708471, G6034815006, Recruitment of First-Time, Tenure-Track Faculty Members, G7016337577, G8227738726, G8594780166, G9000076341, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4389955916