Cisplatin is one of the most potent anticancer agents, with clinical activity against a variety of solid tumors, including melanoma. Combinations of the platinum analogues cisplatin and carboplatin are commonly used and well-tolerated first and second-line therapeutic regimens recently investigated in multicenter randomized trials for advanced metastatic melanoma. However, melanoma is relatively resistant to chemotherapy with response rates to single-agent and polychemotherapy combinations ranging from 7-25%. Resistance to platinum-based drugs is defined by nonresponse of patients with initial treatment, and the development of progressive disease. Despite these obstacles, platinum-based combinations remain a routine first line of chemotherapy for advanced melanoma. It is therefore critical to understand the mechanisms of resistance in order to improve treatment outcomes. Although resistance to platinum based drugs is multifactorial, DNA repair plays a central role in platinum resistance. Nucleotide excision repair (NER) is the major DNA repair pathway for platinum adduct removal and repair of DNA damage. The significance of NER is highlighted by in vitro data that clearly show that a defect in this pathway results in hypersensitivity to platinum-based drugs, and that restoration of NER integrity re-establishes sensitivity to normal levels. The current study was designed to evaluate whether a decrease in overall NER capacity reflected in mRNA expression patterns of melanoma tumor tissue is associated with increased survival of individuals, and whether this correlates with genetic polymorphisms in the NER pathway. We have developed a custom Illumina GoldenGate 384 SNP panel that includes genes for the NER family as well as GSTP1 and ABCB1 that are involved in metabolism and transport of platinum compounds. We have also developed a custom Illumina DASL panel to evaluate gene expression in 128 DNA repair genes. DNA and total RNA were extracted from FFPE tissue sections from 55 melanoma tumors. The overall follow-up time in months (mean ± SD, range) was 12.7±12.1 (0.9-61.3). Cox regression analysis was carried out to test for associations of gene expression and genotypes with survival. Differential expression of POLM, MGMT, RAD23A, CDK7, CCND1, RAD51C, RAD50, POLH, MSH3 genes were significantly associated with survival. SNPs from ABCB1, ERCC2, GSTP1, GTF2H3, OGG1, RAD23B, RPA3, XPA, XPC and XPF were significantly associated with survival. This preliminary data showing an association between genetic variability in the NER pathway and response to drugs that target this pathway is promising. The current study evaluates important questions that have not been addressed to date in melanoma and have potential implications in ultimately improving the efficacy of chemotherapy treatment. These findings require validation in a larger sample size. Supported in part by NIH 5 UL1 RR024153.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4855.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO