RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non–Small-Cell Lung Cancer

University of South Florida, Tampa, Florida, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2006; 24(29):4731-7. DOI: 10.1200/JCO.2006.06.1101
Source: PubMed


RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.
We constructed genetically modified lung cancer cell lines with increased and decreased RRM1 expression to investigate the in vitro 50% inhibitory concentration (IC50) for gemcitabine, cisplatin, and carboplatin. A prospective phase II clinical trial in patients with locally advanced non-small-cell lung cancer was conducted with pretreatment tumor collection for determination of RRM1 and ERCC1 expression by real-time reverse transcriptase polymerase chain reaction. The levels of gene expression were correlated with tumor response after two cycles of gemcitabine and carboplatin.
In cell lines with a genetically engineered 15-fold RRM1 expression range, the gemcitabine IC50 had a 100-fold range, and the cisplatin and carboplatin IC50 had a two-fold range. They were highest in constructs with high RRM1 expression. In the prospective clinical trial, RRM1 expression was significantly (P = .002) and inversely correlated (r = -0.498) with disease response. ERCC1 expression showed a similar trend (P = .099).
The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.


Available from: George R. Simon, Mar 27, 2016
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    • "[16] The RRM1 gene encodes the regulatory subunit of ribonucleotide reductase, an essential enzyme that catalyses the reduction of ribonucleoside diphosphates to deoxyribonucleotides which is required for the DNA synthesis. Increased level of RRM1 enables cells to more efficiently repair DNA damage, resulting in resistance to gemcitabine based therapy.[17][18] The function of the ERCC1 protein is predominantly the nucleotide excision repair of damaged DNA, a process that removes DNA adducts caused by platinum drugs.[19] "
    [Show abstract] [Hide abstract] ABSTRACT: We propose to assess the therapeutic value of biomarker-guided individualized chemotherapy in patients with metastasizing lung adenocarcinoma. In this study, we used primary cells from pleural effusions from sixteen patients diagnosed with adenocarcinomas originating in the lung and from four patients with no malignant diagnosis. The ex vivo drug sensitivity of primary cells was assessed for 32 chemotherapeutical drugs. Linear regression analyses were performed to examine possible correlations between the drug sensitivity, overall survival and expression of ERCC1 and RRM1. The ex vivo drug sensitivity profiles of the patients revealed considerable heterogeneity in drug response. Vinblastine, vinorelbine, paclitaxel and actinomycin D showed high efficiency against 50% of the tested primary cells. Significant correlation was detected between the ex vivo sensitivity to platinum based drugs and gemcitabine and the level of ERCC1 and RRM1. No significant correlation was however seen between overall survival and drug sensitivity. The heterogeneity of the drug response suggests that optimal care of the adenocarcinoma patients should include the determination of drug sensitivity of the primary cells and would benefit to use personalized therapy.
    Full-text · Article · Mar 2015 · Genes & cancer
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    • "An increased level of RRM1 enables cancer cells to more efficiently repair DNA damage caused by chemotherapy, resulting in resistance to gemcitabine. In fact, RRM1 is believed to be the predominant cellular determinant of the efficacy of the nucleoside analogue gemcitabine [15]. For instance, a meta-analysis of Gong et al. [16] has shown that RRM1-low or RRM1-negative advanced NSCLC is associated with a higher response rate to gemcitabine-containing regimen and a better prognosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose To assess the therapeutic value of biomarker-guided chemotherapy in patients with advanced non-small cell lung cancer (NSCLC).MethodsEighty-five NSCLC patients at stage IIIb or IV were divided into two groups based on the feasibility of biomarker analysis. Group A included patients with biomarker data (n = 41); Group B were patients without biomarker results (n = 44). Tumor samples obtained by fiberoptic bronchoscopy and computerized tomography-guided needle biopsy were analyzed by immunohistochemistry for intratumoral level of excision repair cross-complementing gene 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and β-tubulin III. Chemotherapy regimens in Group A were determined according to the status of molecular signatures, whereas a standard gemcitabine plus cisplatin regimen was used for Group B. Tumor response, patient survival, and adverse effects were monitored for both groups.ResultsThe overall response rate, defined as complete response plus partial response, was 56.1 % for Group A, significantly higher than that in Group B (31.8 %; P = 0.024). The median progression-free survival (PFS) time was 5.2 months for Group A, significantly longer than that of Group B (4.1 months; P = 0.026). The 1-year survival rate of Group A was 65.9 %, significantly higher than that of Group B (40.9 %; P = 0.021), whereas the median overall survival times were 13.5 versus 12.5 months for Groups A and B, respectively (P = 0.483). The adverse effects in the two groups were essentially the same.ConclusionsBiomarker-tailored chemotherapy based on ERCC1, RRM1, and β-tubulin III expression showed significantly increased response rate, median PFS time, and 1-year survival rate in patients with NSCLC.
    Preview · Article · Aug 2014 · Cancer Chemotherapy and Pharmacology
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    • "Fan et al. [21] suggested hRRM1 as a tumor suppressor decreased development of tumors and metastasis when they observed hRRM1 overexpression in Ras-transformed mouse fibroblasts. Zhou et al. [22] showed that overexpression of hRRM1 inhibited the invasiveness of human oropharyngeal carcinoma KB cells, and Bepler et al. [23] suggest that overexpression of hRRM1 is correlated with resistance to gemcitabine-based therapy. Gautam and Bepler [24] showed a protective effect of hRRM1 overexpression in carcinogen-induced lung tumors and increased survival of transgenic mice. "
    [Show abstract] [Hide abstract] ABSTRACT: Head and neck squamous epithelial cell cancer (HNSCC), the world’s fifth most common type of cancers, is associated with short life expectancy and high death rates if not detected in early stages. The aim of this study was to investigate hRRM1 and p53R2 gene polymorphisms by using real-time PCR technique in patients with head and neck cancer. In total, 87 patients with head and neck malignancies and 87 control group who have not any malignancies were included in the study between January 2011 and February 2012 in Istanbul University Faculty of Medicine Department of ORL. In the study, real-time PCR was used to detect hRRM1 (rs12806698 C/A) and p53R2 (rs2290707 G/T) gene polymorphisms in Turkish HNSCC patients and healthy individuals. Genomic DNA isolation was performed according to the kit protocol with spin column. LightCycler 1.5 system was used to perform SNP genotyping using hybridization probes consisting of 3′-fluorescein and a 5′-LightCycler Red labeled pair of oligonucleotide probes. There were significant differences in the distribution of hRRM1 genotypes. Frequency of individuals with hRRM1 AA genotype was higher in patients with less differentiation when compared with well differentiation [p 0.025, Fisher’s exact test, odds ratio (OR) 0.140, 95 % confidence intervals (CI) 0.024–0.797]. It is observed that A allele carriers have nearly twofold risk for development of the disease (p = 0.022; χ 2 5.24; OR 2.02, 95 % CI 1.10–3.72).
    Full-text · Article · Jul 2014 · Medical Oncology
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