MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage.

Sophia F Magkouta,Apostolos G Pappas,Ioannis S Pateras,Marianthi P Iliopoulou,Ioannis T Kalomenidis,Panagiotis C Agioutantis,Chrysavgi N Kosti,Photene C Vaitsi,Heleni V Loutrari,Vassilis G Gorgoulis,Charalampos A Moschos

doi:10.1172/jci.insight.134885

Abstract

Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor's response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.

Highlights

Oxidative stress from elevated reactive oxygen species (ROS) as well as insufficient redox regulation is a common phenotype of many cancers [1]
We propose a model of intercellular signaling among tumor cells and bystander tumor endothelium
We investigated whether MTH1 inhibition would halt mesothelioma progression in vivo

Summary

Introduction

Oxidative stress from elevated reactive oxygen species (ROS) as well as insufficient redox regulation is a common phenotype of many cancers [1]. Tumor cells adapt to such conditions by upregulation of the MTH1 (NUDT1) gene. This enzyme sanitizes their oxidized dNTP pools and, prevents incorporation of damaged nucleotides during DNA replication that would otherwise lead to DNA damage and cell death [3,4,5,6]. MTH1 is, crucial for tumor cell survival while it is nonessential for normal cells. This property makes it an appealing target for cancer therapy. Several MTH1 inhibitors have been designed and successfully tested in melanoma, colorectal, and breast cancer xenografts [3, 6,7,8]. Karonudib (TH1579), the most potent inhibitor of the enzyme, is already under phase I clinical testing (Clinicaltrial.gov, NCT03036228)

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Conclusion