Platinum-based
chemotherapies, including
oxaliplatin, are a mainstay in the management of solid
tumors and induce cell death by forming intrastrand dinucleotide
DNA adducts. Despite their common use, they are highly toxic, and approximately half of
cancer patients have
tumors that are either intrinsically resistant or develop resistance. Previous studies suggest that this resistance is mediated by variations in DNA repair levels or net drug influx. Here, we aimed to better define the roles of nucleotide excision repair and DNA damage in
platinum chemotherapy resistance by profiling DNA damage and repair efficiency in seven
oxaliplatin-sensitive and three
oxaliplatin-resistant
colorectal cancer cell lines. We assayed DNA repair indirectly as toxicity and directly measured bulky adduct formation and removal from the genome by slot blot and repair capacity in an excision assay, and used excision repair sequencing (XR-seq) to map repair events genome-wide at single-
nucleotide resolution. Using this combinatorial approach and proxies for
oxaliplatin-DNA damage, we observed no significant differences in repair efficiency that could explain the relative sensitivities and
chemotherapy resistances of these cell lines. In contrast, the levels of
oxaliplatin-induced DNA damage were significantly lower in the resistant cells, indicating that decreased damage formation, rather than increased damage repair, is a major determinant of
oxaliplatin resistance in these cell lines. XR-seq-based analysis of gene expression revealed up-regulation of membrane transport pathways in the resistant cells, and these pathways may contribute to resistance. In conclusion, additional research is needed to characterize the factors mitigating cellular DNA damage formation by
platinum compounds.