The RRM1 gene has been known for its role as the regulatory subunit of ribonucleotide reductase (RR). We have discovered novel functions for RRM1. It suppresses carcinogen-induced lung tumorigenesis. RRM1 also suppresses tumor progression as demonstrated by decreased cellular migration and invasion in vitro and suppression of metastasis formation in a syngeneic mouse model resulting in increased animal survival. In patients with NSCLC, overall survival (OS) and disease-free survival (DFS) are substantially longer for those with high levels of expression as compared to those with low levels of expression. We had found that ERCC1 expression was likewise significantly associated with OS and DFS, and these data were recently confirmed in a very large independent dataset by a separate group of investigators using standard immunohistochemistry (IHC). In terms of its impact on therapy, RRM1 is the major cellular determinant of chemotherapeutic efficacy for gemcitabine. We have demonstrated this directly in vitro through genetic manipulation of RRM1 expression and in vivo through showing an inverse correlation between RRM1 expression and patients'response to gemcitabine/carboplatin chemotherapy. In addition, we observed a similar but less convincing association between ERCC1 expression and tumor response. Finally, we have completed a single institution phase II trial in patients with advanced NSCLC, where the decision on a chemotherapy doublet was based on tumoral RRM1 expression (whether or not gemcitabine was used) and ERCC1 expression (whether or not platinum was used). The outcome of patients on the trial was extremely encouraging with a 1-year survival of 59%. Most recently, we found a strong and convincing correlation between tumoral RRM1 and ERCC1 expression. In our latest analysis on an association between prognosis and expression of both genes, it was the group of patients with high expression of both genes that had a favorable outcome after surgical resection. This group accounts for 30% of all patients with early-stage NSCLC. These results are the basis for our hypothesis that RRM1 is an important regulator of proliferation, survival, and therapeutic efficacy in NSCLC. The primary focus of this project is to integrate RRM1 into current clinical decision-making, to understand the mechanism of coordinate RRM1 and ERCC1 expression, and to generate tools required for optimization of RRM1-directed therapeutic interventions.

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Prior work has demonstrated the prognostic and predictive values of RRM1 and ERCC1 for survival of patients with resected non-small-cell lung cancer and for disease response to gemcitabine and platinum respectively. The purpose of this proposal to valid these data in large datasets of resected patients, to prospectively utilize RRM1 and ERCC1 gene expression values for therapeutic decisions, and to conduct studies elucidating the mechanism of gene expression and function.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Biomarkers Study Section (CBSS)
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Timmer, William C
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Wayne State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Vaezi, Alec E; Bepler, Gerold; Bhagwat, Nikhil R et al. (2014) Choline phosphate cytidylyltransferase-? is a novel antigen detected by the anti-ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas. Cancer 120:1898-907
Zhang, Yingtao; Li, Xin; Chen, Zhengming et al. (2014) Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine. PLoS One 9:e91186
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Bepler, Gerold; Williams, Charles; Schell, Michael J et al. (2013) Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 31:2404-12
Chen, Wei; Bepler, Gerold (2013) A Method for Biomarker Directed Survival Prediction in Advanced Non-Small-Cell Lung Cancer Patients Treated with Carboplatin-Based Therapy. J Pers Med 3:
Zhou, Jun; Chen, Zhengming; Malysa, Agnes et al. (2013) A kinome screen identifies checkpoint kinase 1 (CHK1) as a sensitizer for RRM1-dependent gemcitabine efficacy. PLoS One 8:e58091
Bepler, Gerold; Olaussen, Ken André; Vataire, Anne-Lise et al. (2011) ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis. Am J Pathol 178:69-78
Chen, Zhengming; Zhou, Jun; Zhang, Yingtao et al. (2011) Modulation of the ribonucleotide reductase M1-gemcitabine interaction in vivo by N-ethylmaleimide. Biochem Biophys Res Commun 413:383-8
Chiappori, Alberto A; Zheng, Zhong; Chen, Tingan et al. (2010) Features of potentially predictive biomarkers of chemotherapeutic efficacy in small cell lung cancer. J Thorac Oncol 5:484-90
Harshman, Lauren C; Bepler, Gerold; Zheng, Zhong et al. (2010) Ribonucleotide reductase subunit M1 expression in resectable, muscle-invasive urothelial cancer correlates with survival in younger patients. BJU Int 106:1805-11

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