RRM1

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Gerold Bepler - One of the best experts on this subject based on the ideXlab platform.

  • A Kinome Screen Identifies Checkpoint Kinase 1 (CHK1) as a Sensitizer for RRM1-Dependent Gemcitabine Efficacy
    PloS one, 2013
    Co-Authors: Jun Zhou, Yingtao Zhang, Zhengming Chen, Agnes Malysa, Paula A. Oliveira, Gerold Bepler
    Abstract:

    Gemcitabine is among the most efficacious and widely used antimetabolite agents. Its molecular targets are ribonucleotide reductase M1 (RRM1) and elongating DNA. Acquired and de novo resistance as a result of RRM1 overexpression are major obstacles to therapeutic efficacy. We deployed a synthetic lethality screen to investigate if knockdown of 87 selected protein kinases by siRNA could overcome RRM1-dependent gemcitabine resistance in high and low RRM1-expressing model systems. The models included genetically RRM1-modified lung and breast cancer cell lines, cell lines with gemcitabine-induced RRM1 overexpression, and a series of naturally gemcitabine-resistant cell lines. Lead molecular targets were validated by determination of differential gemcitabine activity using cell lines with and without target knock down, and by assessing synergistic activity between gemcitabine and an inhibitor of the lead target. CHK1 was identified has the kinase with the most significant and robust interaction, and it was validated using AZD7762, a small-molecule ATP-competitive inhibitor of CHK1 activation. Synergism between CHK1 inhibition and RRM1-dependent gemcitabine efficacy was observed in cells with high RRM1 levels, while antagonism was observed in cells with low RRM1 levels. In addition, four cell lines with natural gemcitabine resistance demonstrated improved gemcitabine efficacy after CHK1 inhibition. In tumor specimens from 187 patients with non-small-cell lung cancer, total CHK1 and RRM1 in situ protein levels were significantly (p = 0.003) and inversely correlated. We conclude that inhibition of CHK1 may have its greatest clinical utility in malignancies where gemcitabine resistance is a result of elevated RRM1 levels. We also conclude that CHK1 inhibition in tumors with low RRM1 levels may be detrimental to gemcitabine efficacy.

  • optimizing gemcitabine efficacy through degradation of RRM1
    Annals of Oncology, 2012
    Co-Authors: Gerold Bepler, Y Zhang
    Abstract:

    ABSTRACT Objectives RRM1 (ribonucleotide reductase M1) is the molecular target and key efficacy determinant of gemcitabine. Gemcitabine binds directly to active sites resulting in irreversible inactivation. Mechanisms that control RRM1 abundance are largely unknown, but may provide an opportunity for optimization of gemcitabine efficacy. Methods and results We have identified that the E3 ubiquitin-protein ligases RNF2 (RING finger protein 2, Ring1B) and Bmi1 (B cell-specific moloney murine leukemia virus insertion site 1) interact with RRM1 using yeast two-hybrid screening. We confirmed that RNF2and Bmi1 interact with RRM1 in vivo by immunoprecipitation. Confocal immunofluorescence microscopy revealed that RNF2 and Bmi1 completely co-localized with RRM1 in nucleus. RRM1 undergoes proteasome-mediated polyubiquitination and degradation. The proteasome inhibitor MG132 blocked the turnover of RRM1. We found that RNF2 and Bmi1 can induce polyubiquitination of RRM1 in vitro and in vivo. Lysine (K) 548 and 224 are major polyubiquitination sites of RRM1. Substitution of the lysine residues 548 and 224, either alone or together, significantly reduced RRM1 polyubiquitination. Depletion of RNF2 and Bmi1 by siRNA increased RRM1 protein level and promoted chemoresistance to gemcitabine in vitro. Conclusions These results establish that RNF2 and Bmi1 are E3 ubiquitin ligases of RRM1 that regulate RRM1 ubiquitination, degradation, and cellular response to gemcitabine. This suggests that RNF2 and Bmi1 might be attractive therapeutic targets to overcome gemcitabine resistance in malignancies. Disclosure All authors have declared no conflicts of interest.

  • abstract 5537 ubiquitination of RRM1 by ring1b rnf2 promotes its degradation and nuclear export
    Cancer Research, 2011
    Co-Authors: Yingtao Zhang, Zhengming Chen, Scott N Freeman, Jun Zhou, Gerold Bepler
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL RRM1 (ribonucleotide reductase M1) is a key enzyme involved in deoxyribonucleotide (dNTP) synthesis and DNA damage repair. It also plays a critical role in acquired resistance to the chemotherapy drug gemcitabine, which directly inhibits the RR holoenzyme. Despite its significant importance, however, the mechanisms that control RRM1 abundance and subcellular localization are unclear. We have identified a ubiquitin E3 ligase, Ring1B (RNF2), as an RRM1-associated protein in a yeast two-hybrid screen. RRM1 interacts with Ring1B both in endogenous and exogenous situations. Additionally, immunofluorescent staining has shown that Ring1B clearly co-localized with RRM1 in a pattern of diffuse nuclear speckles. We found that the protein level of RRM1 is regulated by a proteasome-mediated degradation pathway. Ring1B induces poly-ubiquitination of RRM1 in vivo. Formation of poly-ubiquitin chains on RRM1 is through both Lys48 (K48) and Lys63 (K63) of the ubiquitin. Our study demonstrates that the cytoplasmic fraction of RRM1 was increased upon Ring1B or ubiquitin overexpression, but significantly decreased after nuclear export inhibition by leptomycin B (LMB). This indicates that RRM1 ubiquitination promotes the translocation of RRM1 from the nucleus to the cytoplasm. We also show that hydrogen peroxide (H2O2) promotes the degradation of RRM1 in dose and time-dependent manners. H2O2 can increase the poly-ubiquitination of RRM1, which suggests that RRM1 ubiquitination may participate in cellular responses to oxidative stress-induced DNA damage repair. In summary, our data propose that Ring1B-induced ubiquitination regulates RRM1 activity through RRM1 degradation and nuclear export. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2011-5537

  • Correlation of RRM1 expression in muscle invasive locally advanced urothelial cancer with age
    Journal of Clinical Oncology, 2009
    Co-Authors: Lauren C. Harshman, Gerold Bepler, Zhong Zheng, John P. Higgins, Genevera I. Allen, Robert Tibshirani, Sandy Srinivas
    Abstract:

    e16021 Background: RRM1, the regulatory subunit of ribonucleotide reductase, plays a role in DNA repair after chemotherapy damage and in gemcitabine metabolism. Prior studies demonstrated a survival benefit to high expression in resected early stage lung cancer and a trend toward longer time to progression with low expression in advanced bladder cancers treated with gemcitabine and cisplatin. We hypothesized that patients with resected locally advanced (T2–4NxM0) urothelial transitional cell carcinoma (TCC) whose tumors had higher RRM1 expression would have longer overall survival (OS). Methods: 84 radical cystectomy specimens with muscle invasive TCC were identified from existing tissue microarrays (TMAs) containing 343 specimens. The medical records of these patients were retrospectively reviewed to confirm pathology and stage. Presence of muscle invasion was required. Specimens were analyzed for RRM1 expression using AQUA. The median value of RRM1 was established a priori as the cutoff for high and low expression. Results: Median age of the patients was 69.3 years. There was near equal distribution of stages: 30%, 38%, and 32% for stage II, III, and IV respectively. The majority were high grade (99%) with no nodal involvement (69%). Median OS was 2.0 years (0–13.1). Median RRM1 expression was 1493.3. Degree of RRM1 expression did not correlate with OS, but when adjusted for age, adding an interaction term, high RRM1 expression in younger patients correlated with increased OS (p = 0.0278). Median OS for high expressors age <69.3 years was 6 years compared to 2.3 years for low expressors. 35% of patients less than 70 years were high expressors. Conclusions: Our results suggest that high RRM1 expression may be a prognostic factor for improved survival in locally advanced TCC patients less than 70 years old. These results deserve further study in a larger prospective analysis with disease-specific survival assessment and correlation with other possible prognostic genes such as ERCC1. [Table: see text]

  • In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-including chemotherapy
    Journal of Clinical Oncology, 2009
    Co-Authors: G. Metro, Zhong Zheng, Alessandra Fabi, Marcella Mottolese, Alvaro N.a. Monteiro, Patrizia Vici, S. Lara Rivera, David Boulware, F. Cognetti, Gerold Bepler
    Abstract:

    1129 Background: Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small cell lung cancer (NSCLC) and pancreatic cancer. We investigated the tumoral levels of RRM1 in a population of metastatic breast cancer (MBC) patients treated with gemcitabine-based regimens. The protein levels of the excision repair cross-complementation group 1 (ERCC1) and breast and ovarian cancer susceptibility gene 1 (BRCA1) were also measured. Methods: Fifty-five patients were treated and followed prospectively from September 2004 to December 2007. Treatment consisted of gemcitabine plus a taxane in 46 patients and gemcitabine plus pegylated liposomal doxorubicin in 9 patients. RRM1, ERCC1, and BRCA1 were determined by automated in situ protein quantification (AQUA v1.6) on a tissue microarray containing triplicate tumor specimens. Results: The average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6–2, 774.1, 74.0–410.3, and 54.4–1, 833.1, respectively. A statistically significant correlation between the levels of expression of all three markers (Spearman's rho > .36; P < 0.007) was observed. There was no significant association between RRM1, ERCC1, or BRCA1 levels and disease response, progression free survival, or overall survival. Conclusions: In tumor specimens from patients with MBC, RRM1, and BRCA1 had a range of expression and pattern of distribution that makes these markers potentially suitable for clinical decision making. In contrast, the relatively narrow range of ERCC1 expression might signify that ERCC1 protein levels are not useful predictors of platinum efficacy in MBC. Consistent with what has been shown in NSCLC, RRM1, ERCC1, and BRCA1 levels were significantly correlated, suggesting that the coexpression of such DNA repair proteins may be universal to epithelial malignancies. The lack of correlation between marker levels and clinical outcome may be explained by the specific chemotherapy combinations used. No significant financial relationships to disclose.

Hua Cheng - One of the best experts on this subject based on the ideXlab platform.

  • RRM1 single nucleotide polymorphism -37C→A correlates with progression-free survival in NSCLC patients after gemcitabine-based chemotherapy
    Journal of hematology & oncology, 2010
    Co-Authors: Song Dong, Ailin Guo, Zhi-hong Chen, Zhen Wang, Xu-chao Zhang, Ying Huang, Zhi Xie, Hong-hong Yan, Hua Cheng
    Abstract:

    The 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. PBMC 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. RRM1 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. The 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.

  • RRM1 single nucleotide polymorphism 37c a correlates with progression free survival in nsclc patients after gemcitabine based chemotherapy
    Journal of Hematology & Oncology, 2010
    Co-Authors: Song Dong, Ailin Guo, Zhi-hong Chen, Zhen Wang, Xu-chao Zhang, Ying Huang, Zhi Xie, Hong-hong Yan, Hua Cheng
    Abstract:

    Background The 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.

M Trypaki - One of the best experts on this subject based on the ideXlab platform.

  • Association of BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression levels between primary tumors and infiltrated regional lymph nodes in patients with resectable non-small cell lung cancer
    The Pharmacogenomics Journal, 2019
    Co-Authors: K Tryfonidis, M Trypaki, C Papadaki, S Assele, E Lagoudaki, J Menis, A Koutsopoulos, E Tsakalaki, M Sfakianaki, B Hasan
    Abstract:

    Differences in gene expression levels between the primary tumors (PTs) and matched regional lymph nodal metastases (LNs) in patients with totally excised non-small cell lung cancer (NSCLC) were explored. Microdissected formalin-fixed paraffin-embedded (FFPE) samples from (PT) and their matched infiltrated LNs, from 239 patients [183 (with matched PT and LNs samples)-case and 56 PT only samples-control cohorts] were analyzed for BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1 , and TXR1 mRNA expression by quantitative real-time polymerase-chain reaction (PCR). Moderately positive correlation between the expression of each gene in the PT and the matched LNs was observed. Concordance rates between the PT and the LNs were: BRCA1 (67.7%), ERCC1 (68.4%), PKM2 (63.4%), RAP80 (68.8%), RRM1 (70.9%), RRM2 (69%), TS (72.9%), TSP1 (69.8%), TXR1 (63.7%). Expression levels and their differences were correlated with Relapse-Free Survival (RFS) and Overall Survival (OS). High BRCA1 PT in patients with squamous histology was associated with increased OS ( p  = 0.036). High TSP1 PT levels were shown to be the only independent prognostic factor for OS and RFS ( p  = 0.023 and p  = 0.007). PKM2 low levels in both PT and matched LNs were associated with better OS irrespective of the underlying histology ( p  = 0.031). RRM1 discordant levels between PT and matched LNs were associated with worse OS in squamous tumors ( p  = 0.019) compared to patients with both low expression in PT and LN. TXR1 high levels in both PT and matched LNs were associated with better OS in patients with squamous tumors ( p  = 0.007).These findings indicate that there is different gene expression between PT and matched LNs which may affect the outcome in early NSCLC and therefore PT’s molecular biology should not be the sole determinant for prognostication.

  • tumor brca1 RRM1 and rrm2 mrna expression levels and clinical response to first line gemcitabine plus docetaxel in non small cell lung cancer patients
    PLOS ONE, 2008
    Co-Authors: Ioannis Boukovinas, Chara Papadaki, Pedro Mendez, Miquel Taron, Dimitris Mavroudis, Anastasios Koutsopoulos, Maria Sanchezronco, Jose Javier Sanchez, M Trypaki, Eustathios Staphopoulos
    Abstract:

    Background Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients.

  • association of tumoral brca1 RRM1 and rrm2 mrna expression levels with clinical responses to front line docetaxel gemcitabine dg chemotherapy in patients with non small cell lung cancer nsclc
    Journal of Clinical Oncology, 2008
    Co-Authors: Chara Papadaki, Ioannis Boukovinas, Dimitris Mavroudis, Anastasios Koutsopoulos, M Trypaki, Efstathios N Stathopoulos, Maria Sfakianaki, V Georgoulias, John Souglakos
    Abstract:

    8112 Background: To investigate the prognostic and predictive value of tumoral BRCA1, RRM1 and RRM2 in clinical outcome of patients with NSCLC treated with the DG regimen. Methods: Tumor samples fr...

Chara Papadaki - One of the best experts on this subject based on the ideXlab platform.

Zhidong Liu - One of the best experts on this subject based on the ideXlab platform.

  • mrna expression and clinical significance of ercc1 brca1 RRM1 tyms and tubb3 in postoperative patients with non small cell lung cancer
    Asian Pacific Journal of Cancer Prevention, 2013
    Co-Authors: Yi Han, Xiao-bin Wang, Ning Xiao, Zhidong Liu
    Abstract:

    Background: To explore mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in tumor tissue of postoperative patients with non-small cell lung cancer (NSCLC). Materials and Methods: Sixty NSCLC patients undergoing radical operation in our hospital from Nov., 2011 to Jun., 2012 were selected. Plasmid standards of ERCC1, BRCA1, RRM1, TYMS and TUBB3 were established and standard curves were prepared by SYBR fluorescent real-time quantitative PCR analysis. Samples from tumor centers were taken to detect mRNA expression of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in cancerous tissue during operation. The total mRNA expression quantities were compared according to different clinical characteristics. Results: The total expression quantities of 5 genotypes from high to low were ERCC1>RRM1>TUBB3>TYMS>BRCA1 in turn. By pairwise comparisons, other differences showed statistical significance ( p 0.05); the low expression rates from high to low were ERCC1>TYMS>TUBB3>TUBB3>RRM1>BRCA1 in turn. The expression quantities of BRCA1, RRM1 and TYMS in males, smokers and patients without adenocarcinoma were all significantly higher than that in females, non-smokers and patients with adenocarcinoma, and significant differences were present ( p<0.05 or p<0.01). In terms of pathological staging, the expression quantities of BRCA1, RRM1 and TYMS in phases Ⅱa~Ⅱb and Ⅲa~Ⅲb had a tendency to be greater than in phases Ⅰ and Ⅳ. Conclusions: Resistance to chemotherapy and sensitivity to targeted therapy differ among patients with NSCLC. Differences in gene expression in different individuals were also revealed. Only according to personalized detection results can individualized therapeutic regimens be worked out, which is a new direction for oncotherapy.

  • mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in postoperative patients with non-small cell lung cancer.
    Asian Pacific journal of cancer prevention : APJCP, 2013
    Co-Authors: Yi Han, Xiao-bin Wang, Ning Xiao, Zhidong Liu
    Abstract:

    To explore mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in tumor tissue of postoperative patients with non-small cell lung cancer (NSCLC). Sixty NSCLC patients undergoing radical operation in our hospital from Nov., 2011 to Jun., 2012 were selected. Plasmid standards of ERCC1, BRCA1, RRM1, TYMS and TUBB3 were established and standard curves were prepared by SYBR fluorescent real-time quantitative PCR analysis. Samples from tumor centers were taken to detect mRNA expression of ERCC1, BRCA1, RRM1, TYMS and TUBB3 genes in cancerous tissue during operation. The total mRNA expression quantities were compared according to different clinical characteristics. The total expression quantities of 5 genotypes from high to low were ERCC1>RRM1>TUBB3>TYMS>BRCA1 in turn. By pairwise comparisons, other differences showed statistical significance (p<0.05 or p<0.01) except for TYMS and TUBB3 (p>0.05); the low expression rates from high to low were ERCC1>TYMS>TUBB3>TUBB3>RRM1>BRCA1 in turn. The expression quantities of BRCA1, RRM1 and TYMS in males, smokers and patients without adenocarcinoma were all significantly higher than that in females, non-smokers and patients with adenocarcinoma, and significant differences were present (p<0.05 or p<0.01). In terms of pathological staging, the expression quantities of BRCA1, RRM1 and TYMS in phases IIa~IIb and IIIa~IIIb had a tendency to be greater than in phases I and IV. Resistance to chemotherapy and sensitivity to targeted therapy differ among patients with NSCLC. Differences in gene expression in different individuals were also revealed. Only according to personalized detection results can individualized therapeutic regimens be worked out, which is a new direction for oncotherapy.

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