Preclinical Development Genetic Variation That Predicts Platinum Sensitivity Reveals the Role of miR-193b in Chemotherapeutic Susceptibility

Platinum agents are the backbone of cancer chemotherapy. Recently, we identified and replicated the role of a single nucleotide polymorphism (SNP, rs1649942) in predicting platinum sensitivity both in vitro and in vivo. Using the CEU samples from the International HapMap Project, we found the same SNP to be a master regulator of multiple gene expression phenotypes, prompting us to investigate whether rs1649942-mediated regulation of miRNAs may in part contribute to variation in platinum sensitivity. To these ends, 60 unrelated HapMap CEU I/II samples were used for our discovery-phase study using high-throughput genome-wide miRNA and gene expression profiling. Examining the relationships among rs1649942, its gene expression targets, genome-wide miRNA expression, and cellular sensitivity to carboplatin and cisplatin, we identified 2 platinum-associated miRNAs (miR-193b and miR-320) that inhibit the expression of 5 platinum-associated genes (CRIM1, IFIT2, OAS1, KCNMA1, and GRAMD1B). We further replicated the relationship between the expression of miR-193b , CRIM1, IFIT2, KCNMA1, and GRAMD1B, and platinum sensitivity in a separate HapMap CEU III dataset. We then showed that overexpression of miR-193b in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin. This relationship was also found in 7 ovarian cancer cell lines fromNCI60 dataset and confirmed in an OVCAR-3 that overexpression of miR-193b leads to increased resistance to carboplatin. Our findings highlight a potential mechanism of action for a previously observed genotype-survival outcome association. Further examination ofmiR-193b in platinum sensitivity in ovarian cancer is warranted. Mol Cancer Ther; 11(9); 1–8. 2012 AACR.