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Published on: April 28, 2021
PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition
Yang Li1, Lacey E Dobrolecki2, Christina Sallas2
1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
Insights
Targeting protein arginine methyltransferases (PRMTs) with inhibitors suppresses ATR, a key DNA repair protein. Combining PRMT5 inhibition with PARP inhibitors shows promise for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Aberrant protein arginine methylation by PRMT1, PRMT4, and PRMT5 is observed in multiple cancers.
- PRMTs play a crucial role in cellular processes, including DNA repair and stress response.
Purpose of the Study:
- To investigate the effects of inhibiting PRMT1, PRMT4, and PRMT5 on cancer cell lines.
- To determine the therapeutic potential of combining PRMT inhibition with PARP inhibitors.
Main Methods:
- Targeted proteomics was employed to analyze protein levels after PRMT inhibition in 12 cancer cell lines.
- The study assessed the impact of PRMT inhibition on ATR levels and DNA replication stress response.
- Synergistic effects of PRMT and PARP inhibitors were evaluated in vitro and in vivo.
Main Results:
- Inhibition of type I and II PRMTs led to the suppression of phosphorylated and total ATR.
- PRMT inhibition resulted in defective DNA replication stress response activation, potentiating PARP inhibitor efficacy.
- Combination therapy of PRMT5 and PARP inhibitors demonstrated improved survival in patient-derived xenografts without observed toxicity.
Conclusions:
- PRMT inhibition, particularly PRMT5, can sensitize tumors to PARP inhibitors.
- The combination of PRMT5 and PARP inhibition represents a potentially well-tolerated and effective therapeutic strategy for various cancers, irrespective of homologous recombination status.
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