Abstract
BackgroundThe ribonucleotide reductase M1 (RRM1) gene encodes the regulatory subunit of ribonucleotide reductase, the molecular target of gemcitabine. The overexpression of RRM1 mRNA in tumor tissues is reported to be associated with gemcitabine resistance. Thus, single nucleotide polymorphisms (SNPs) of the RRM1 gene are potential biomarkers of the response to gemcitabine chemotherapy. We investigated whether RRM1 expression in peripheral blood mononuclear cells (PBMCs) or SNPs were associated with clinical outcome after gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients.MethodsPBMC samples were obtained from 62 stage IIIB and IV patients treated with gemcitabine-based chemotherapy. RRM1 mRNA expression levels were assessed by real-time PCR. Three RRM1 SNPs, -37C→A, 2455A→G and 2464G→A, were assessed by direct sequencing.ResultsRRM1 expression was detectable in 57 PBMC samples, and SNPs were sequenced in 56 samples. The overall response rate to gemcitabine was 18%; there was no significant association between RRM1 mRNA expression and response rate (P = 0.560). The median progression-free survival (PFS) was 23.3 weeks in the lower expression group and 26.9 weeks in the higher expression group (P = 0.659). For the -37C→A polymorphism, the median PFS was 30.7 weeks in the C(-)37A group, 24.7 weeks in the A(-)37A group, and 23.3 weeks in the C(-)37C group (P = 0.043). No significant difference in PFS was observed for the SNP 2455A→G or 2464G→A.ConclusionsThe RRM1 polymorphism -37C→A correlated with PFS in NSCLC patients treated with gemcitabine-based chemotherapy. No significant correlation was found between PBMC RRM1 mRNA expression and the efficacy of gemcitabine.
Highlights
The ribonucleotide reductase M1 (RRM1) gene encodes the regulatory subunit of ribonucleotide reductase, the molecular target of gemcitabine
Venous blood was collected before chemotherapy and gene expression was analyzed, but no association was found between RRM1 mRNA expression in peripheral blood mononuclear cells (PBMCs) and the efficacy of gemcitabine treatment
We found that the intron 1 (CA) repeat genetic polymorphisms of the epidermal growth factor receptor (EGFR) gene were correlated with EGFR protein expression and clinical response in non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitor[18]
Summary
The ribonucleotide reductase M1 (RRM1) gene encodes the regulatory subunit of ribonucleotide reductase, the molecular target of gemcitabine. We investigated whether RRM1 expression in peripheral blood mononuclear cells (PBMCs) or SNPs were associated with clinical outcome after gemcitabinebased chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. The molecular target of gemcitabine is ribonucleotide reductase [5]. This enzyme catalyzes the rate-limiting step in deoxyribonucleotide formation and is the only known enzyme that converts ribonucleotides to deoxyribonucletides, which are required for DNA polymerization and repair [6]. The RRM1 gene encodes the regulatory subunit of ribonucleotide reductase; diphosphorylated gemcitabine (dFdDDP) indirectly inhibits DNA synthesis through the inhibition of RRM1 [7]
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