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

Claudia Dominici,Zhenbao Yu,Laura Sesma-Sanz,Stéphane Richard,Noël J.-M Raynal,Nicolas Sgarioto,Jean-Yves Masson

doi:10.1186/s13148-021-01037-1

Abstract

BackgroundNon-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.ResultsAmong 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.ConclusionsThese 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.

Highlights

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide
Cell viability screen with epigenetic/anticancer library identifies compounds that synergize with the type I Protein arginine methyltransferase (PRMT) inhibitor, MS023 Since PRMT overexpression has been implicated in various human cancers and deficiency of PRMT activity can inhibit cancer cell proliferation and lead to cell death [21], we initiated a small molecule library screen to identify epigenetic/anticancer drugs, which can cause synthetic lethality in combination with MS023, an inhibitor of type I PRMTs [23]
(See figure on page.) Fig. 7 Treatment with MS023 renders PARP inhibitor (PARPi)-resistant PEO4 ovarian adenocarcinoma cells sensitive to BMN-673. a, b Cell viability curves from PEO1 (a) and PEO4 (b) cells treated with a range of BMN-673 (3.75–60 nM) alone, or in combination with 0.125, 0.25, 0.5, or 1 μM MS023. c, d The open-source R package SynergyFinder was used to visualize the dose–response of the combination of BMN-673 and MS023 in PEO1 (c) and PEO4 (d) cells and to calculate Bliss synergy scores

Summary

Introduction

Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide. Dominici et al Clin Epigenet (2021) 13:54 oncogenic pathways have been identified in patients with NSCLC with varying degrees of penetration, such as aberrations in receptor tyrosine kinase signalling, mTOR signalling, and components of the cell cycle [4, 5]. While deficiencies in these well-studied pathways create an opening for targeted molecular therapies, the complex etiology of NSCLC presents a challenge in developing a unified therapy that can be extended to a broad range of patients. The success observed with targeting DNA methyltransferases (DNMTs) in combination with histone deacetylases (HDACs) in NSCLC provides a rationale for uncovering other combinations of epigenetic modifiers, which can be developed into effective therapies [10, 11]

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