2. Academic Validation
  3. Synergistic effects of type I PRMT and PARP inhibitors against non-small cell lung cancer cells

Synergistic effects of type I PRMT and PARP inhibitors against non-small cell lung cancer cells

  • Clin Epigenetics. 2021 Mar 10;13(1):54. doi: 10.1186/s13148-021-01037-1.
Claudia Dominici 1,  Nicolas Sgarioto 2,  Zhenbao Yu 1,  Laura Sesma-Sanz 3,  Jean-Yves Masson 3,  Stéphane Richard 4,  Noël J-M Raynal 5
Affiliations

Affiliations

  • 1 Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology and Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montréal, QC, H3T 1E2, Canada.
  • 2 Département de Pharmacologie et Physiologie, Université de Montréal, and Research Centre of the Sainte-Justine University Hospital, Montréal, QC, H3T 1C5, Canada.
  • 3 Genome Stability Laboratory, CHU de Québec Research Center, Oncology Division, Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, 9 McMahon, Québec, QC, G1R 3S3, Canada.
  • 4 Segal Cancer Center, Lady Davis Institute for Medical Research and Gerald Bronfman Department of Oncology and Departments of Biochemistry, Human Genetics and Medicine, McGill University, Montréal, QC, H3T 1E2, Canada. stephane.richard@mcgill.ca.
  • 5 Département de Pharmacologie et Physiologie, Université de Montréal, and Research Centre of the Sainte-Justine University Hospital, Montréal, QC, H3T 1C5, Canada. noel.raynal@umontreal.ca.
PMID: 33691794 DOI: 10.1186/s13148-021-01037-1
Abstract

Background: Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide. Current therapies for NSCLC include chemotherapy, immunotherapy, and targeted molecular agents such as tyrosine kinase inhibitors and epigenetic drugs such as DNA Methyltransferase inhibitors. However, survival rates remain low for patients with NSCLC, especially those with metastatic disease. A major cause for therapeutic failure is drug resistance, highlighting the need for novel therapies and combination strategies. Given that epigenetic modulators such as protein arginine methyltransferases (PRMTs) are frequently overexpressed in cancers, PRMT inhibitors are a promising class of Cancer therapeutics. We screened a library of epigenetic and Anticancer drugs to identify compounds that would synergize with MS023, a type I PRMT inhibitor, in decreasing the viability of methylthioadenosine Phosphorylase (MTAP)-negative NSCLC cells.

Results: Among 181 compounds, we identified PARP inhibitors (PARPi) as having a strong synergistic interaction with type I PRMT inhibition. The combination of MS023 and the PARP Inhibitor BMN-673 (Talazoparib) demonstrated strong synergistic interaction at low nanomolar concentrations in MTAP-negative NSCLC cell lines A549, SK-LU-1 and HCC4006. The re-introduction of MTAP decreased the sensitivity of the combination therapy in A549. The combination therapy resulted in elevated γ-H2AX foci indicating increased DNA damage causing decreased cell viability. Lastly, the combination therapy was effective in PARPi resistant ovarian Cancer cells, suggesting that type I PRMT inhibitors could mitigate PARPi resistance, thus potentially having an important clinical impact for Cancer treatment.

Conclusions: These findings identify a novel Cancer drug combination therapy, which is more potent than the separate single-agent therapies. Thus, combining PARP inhibitors and type I PRMT inhibitors represents a new therapeutic opportunity for MTAP-negative NSCLC and certain Cancer cells resistant to PARP inhibitors.

Keywords

And cytotoxic; DNA damage; Drug resistance; MTAP; Non-small cell lung cancer cells; PARP inhibitors; Synergy; Type I PRMT inhibitors.

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