Pharmacogenetics of platinum-based chemotherapy in non-small cell lung cancer: predictive validity of polymorphisms of ERCC1

Abstract

ABSTRACTIntroduction: The efficacy of platinum-based chemotherapy for patients with non-small cell lung cancer (NSCLC) is limited by chemoresistance. Platinum drugs damage DNA by introducing intrastrand and interstrand crosslinks which result in cell death. Excision repair cross-complementing 1 (ERCC1) is a member of the nucleotide excision repair (NER) pathway which erases such defects. Single nucleotide polymorphisms (SNPs) in ERCC1 impair this activity and have been suggested to predict the response to chemotherapy.Area covered: Among the polymorphisms of proteins involved in uptake, metabolism, cytotoxicity and efflux of platinum drugs, codon 118 C/T and C8092A in ERCC1 are the best characterized SNPs studied for their predictive power. Here, the divergent results for studies of these markers in NSCLC are summarized and the reasons for this contradictory data discussed.Expert opinion: Cytotoxicity of platinum compounds comprise complex cellular processes for which DNA repair may not constitute the rate limiting step. These drugs are administered as doublets to histologically diverse patients and, furthermore, the NER pathway in ERCC1 wildtype cohorts may be still impaired by the chemotherapeutics applied. At present, assessment of a limited number of polymorphism in DNA repair proteins is not reliably associated with response to treatment in NSCLC patients.