Upregulation of Thymidylate Synthase Induces Pemetrexed Resistance in Malignant Pleural Mesothelioma.

Yuzo Sato,Hideki Makinoshima,Masaru Tomita,Atsushi Ochiai,Tomoyoshi Soga

doi:10.3389/fphar.2021.718675

Abstract

Malignant pleural mesothelioma (MPM) is an invasive malignancy that develops in the pleural cavity, and antifolates are used as chemotherapeutics for treating. The majority of antifolates, including pemetrexed (PMX), inhibit enzymes involved in purine and pyrimidine synthesis. MPM patients frequently develop drug resistance in clinical practice, however the associated drug-resistance mechanism is not well understood. This study was aimed to elucidate the mechanism underlying resistance to PMX in MPM cell lines. We found that among the differentially expressed genes associated with drug resistance (determined by RNA sequencing), TYMS expression was higher in the established resistant cell lines than in the parental cell lines. Knocking down TYMS expression significantly reduced drug resistance in the resistant cell lines. Conversely, TYMS overexpression significantly increased drug resistance in the parental cells. Metabolomics analysis revealed that the levels of dTMP were higher in the resistant cell lines than in the parental cell lines; however, resistant cells showed no changes in dTTP levels after PMX treatment. We found that the nucleic acid-biosynthetic pathway is important for predicting the efficacy of PMX in MPM cells. The results of chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assays suggested that H3K27 acetylation in the 5′-UTR of TYMS may promote its expression in drug-resistant cells. Our findings indicate that the intracellular levels of dTMP are potential biomarkers for the effective treatment of patients with MPM and suggest the importance of regulatory mechanisms of TYMS expression in the disease.

Highlights

Malignant pleural mesothelioma (MPM) is a locally invasive and fatal malignancy associated with asbestos exposure (Liu et al, 2017; Yap et al, 2017)
The IC50 value was defined as the dose of PMX required to reduce the viability of MPM cells by 50%
This study confirmed that acquired PMX resistance in MPM cells was caused by increased thymidylate synthase (TYMS) expression

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a locally invasive and fatal malignancy associated with asbestos exposure (Liu et al, 2017; Yap et al, 2017). Treatment with a combination of PMX and cisplatin, along with vitamin supplements, resulted in a superior survival period, time to progression, and response rates compared to treatment with cisplatin alone in patients with MPM (Vogelzang et al, 2003; Scagliotti et al, 2008). The median survival period was approximately 12 months, and the response rate was 41.3% after treatment with PMX and cisplatin (Vogelzang et al, 2003). This indicates that approximately 60% of patients with MPM are resistant to PMX and cisplatin (Zhu et al, 2016)

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