Thymidylate synthase inhibitors for thoracic tumors

Abstract

Thymidylate synthase (TS) is a valid target for treatment of non-small cell lung cancer (NSCLC) and mesothelioma (MPM). The TS inhibitor pemetrexed (PMX) is now commonly used in combination with cisplatin (CDDP) or carboplatin, in the first-line setting for both of these lethal diseases. A combination of another TS inhibitor, Tomudex with CDDP, demonstrated similar activity in MPM patients. However, the efficacy of TS inhibitors is limited by uptake, metabolism and target affinity. While uptake of most antifolates is mediated by the reduced folate carrier, PMX is also a good substrate for the proton-coupled folate transporter (PCFT), which displays optimal activity at the acidic pH of the tumor microenvironment. NSCLC and MPM have a variable expression of PCFT, which might be caused by the differential methylation status of the PCFT promoter, resulting in decreased anticancer activity. PMX and TDX activity also depends on polyglutamylation, catalyzed by folylpolyglutamate synthetase (FPGS), which results in intracellular retention and thus enhanced cytotoxicity. We demonstrated that resistance to the classical antifolate methotrexate in human leukemia cells with a marked loss of FPGS activity was associated with impaired splicing of FPGS pre-mRNA. Moreover, we recently showed that the sensitivity of MPM patients to PMX-carboplatin is related to tumor TS expression. Patients with low TS mRNA levels had a significantly longer overall survival (20 vs. 7 months) compared with patients with high expression. Intriguingly, recent trials demonstrated that histology plays an important role in the sensitivity of NSCLC patients, and PMX-CDDP is now approved only for adenocarcinoma patients. These results might be partly explained by the higher TS expression detected in lung tumors of squamous histology. In summary, the clinical success of TS inhibitors may depend on biomarker-driven patient selection, and further studies should evaluate the genetic/epigenetic factors involved in the modulation of these biomarkers in the preclinical and clinical setting.

Keywords

• mesothelioma
• non-small cell lung cancer
• pemetrexed
• pharmacogenetics
• thymidylate synthase