PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

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

doi:10.1016/j.xcrm.2023.101326

PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition

Cell Rep Med. 2023 Dec 19;4(12):101326. doi: 10.1016/j.xcrm.2023.101326.

Authors

Yang Li¹, Lacey E Dobrolecki², Christina Sallas², Xudong Zhang³, Travis D Kerr⁴, Deepa Bisht¹, Yalong Wang¹, Sharad Awasthi¹, Babita Kaundal¹, Siqi Wu⁵, Weiyi Peng⁶, Marc L Mendillo⁷, Yiling Lu⁸, Collene R Jeter¹, Guang Peng⁵, Jinsong Liu³, Shannon N Westin⁹, Anil K Sood⁹, Michael T Lewis², Jishnu Das¹⁰, S Stephen Yi¹¹, Mark T Bedford¹, Daniel J McGrail¹², Nidhi Sahni¹³

Affiliations

¹ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
³ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
⁷ Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Center for Systems Immunology, Department of Immunology, and Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA; Interdisciplinary Life Sciences Graduate Programs (ILSGP), College of Natural Sciences, The University of Texas at Austin, Austin, TX, USA; Oden Institute for Computational Engineering and Sciences (ICES), The University of Texas at Austin, Austin, TX, USA; Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA.
¹² Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: mcgraid@ccf.org.
¹³ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX, USA. Electronic address: nsahni@mdanderson.org.

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.

Keywords: DNA replication stress; PARP inhibitors; PRMT inhibitors; arginine methylation; breast cancer; ovarian cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Arginine / metabolism
Cell Line
DNA Replication
Humans
Neoplasms* / drug therapy
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Protein-Arginine N-Methyltransferases / therapeutic use
Repressor Proteins / metabolism

Substances

Poly(ADP-ribose) Polymerase Inhibitors
Arginine
PRMT1 protein, human
Protein-Arginine N-Methyltransferases
Repressor Proteins
PRMT5 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding