Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells.

Efficacy of camptothecins (CPTs) such as irinotecan has been recognized in chemotherapy of cancers including melanoma. However, the majority of responding patients will gradually acquire drug resistance. Little is known of the genes responsible for the acquired CPT-resistance in cancer. To gain global insight into acquired CPT-resistance, we established irinotecan-resistant clones derived from melanoma cells and compared their whole genomes by high resolution array-CGH. A novel gain at 14q23.2-31.1 was revealed by alignment of whole genome profiles of parental cell line and irinotecan-resistant clones. Further analysis of this amplicon indicates that it encompassed genes involved in DNA repair (RAD51L, MLH3), reactive oxygen species (GPX2, CSTZ1, NGB, RDH11, ZADH1), and transportome (ABCD4, ATP6V1D, SLC10A6). Moreover, losses were also detected at the loci of topoisomerases (TOP1, SPO11, TOP3B) as well as at the loci of genes guarding chromosomal stability (TP53, ZW10, H2AFX, CHK1, CCDN1, MCM5, CENPB, DNMT3B), which would facilitate the development of drug resistance. Furthermore, quantitative real-time PCR demonstrated that mRNA changes of selected novel genes (CENPB, H2AFX, MCM5, ZADH1 and NGB) in irinotecan-resistant clones vs. parental clone were in agreement with array-CGH results. Taken together, our data suggest that genes involved in genome stability may greatly contribute to the development of CPTs-resistance. In addition, genes located at 14q23.3-31.1 would be promising targets to overcome acquired CPT-resistance in melanoma.