Background: The standard treatment for epithelial ovarian cancer (EOC) patients with advanced disease is initial debulking surgery followed by carboplatin-paclitaxel combination therapy. Unfortunately, even with modern chemotherapy, most patients with advanced disease relapse and die of EOC. One of the biggest challenges in the treatment of EOC is the large inter-patient variation in clinical response and toxicity observed for taxane and platinum therapies. Purpose: To determine pharmacogenomic markers related to carboplatin-paclitaxel therapy with 33 Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCLs) derived from EOC patients for which genome-wide genetic information exists. Methods: The 33 LCLs were treated with increasing concentrations of carboplatin and/or paclitaxel, followed by MTT cytotoxicity and Caspase3/7 assays. Using the measurements of MTT absorbance or Caspase3/7 fluorescence, dose response curves were fit to estimate the in vitro drug response (MTT or caspase3/7) for each LCL and treatment (paclitaxel, carboplatin, and combination) using the inflection point of the fitted curve (i.e.., the MTT IC50 or effective dose that kills 50% of the cells). The six in vitro phenotypes where then associated with genome-wide SNP data, imputed up to the markers in the 1000 Genomes Project. Results: Genetic association analysis of carboplatin, paclitaxel and combination therapy cell viability, as measured by MTT, found one SNP, rs202167095 within HS3ST4, in common with all three phenotypes (p < 0.0001). HS3ST4 is regulated by TRF2 and activates natural killer cells. Furthermore, TRF2 maintains telomere integrity and is involved in activating DNA damage response (DDR) pathway.. Similarly, three SNPs were found to be associated with the three Caspase3/7 activities: SNPs on chromosome 3 (rs13098237 and rs13098239), and a SNP on chromosome 10 (rs138004421 within LINC00858). Lastly, SNPs in the following genes were associated with carboplatin IC50 with p < 1x10-6 (i.e., the top associated SNPs with any drug response phenotype): JAKMIP3 (p=2.3x10-7), TSHZ3 (p = 4.9x10-7) and TGFA (p=3.6x10-7). JAKMIP3 has been implicated in some cancers and interacts with other janus kinases and JAK-STAT pathways, while TSHZ3 inhibits the expression of CASP4, thus limiting cell apoptosis. Lastly, TGFA codes for a growth factor that is a ligand for epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. Conclusions: Identifying genetic loci associated with response to platinum-taxane therapies will ultimately improve clinicians' ability to tailor therapy decisions for EOC patients. This research discovered novel candidate genes for which further research is needed to understand the mechanism by which they impact clinical response.
Citation Format: Brooke L. Fridley, Taraswi M. Ghosh, Alice Wang, Ellen L. Goode, Jatinder Lamba. In vitro pharmacogenomic study of ovarian cancer finds novel genetic variants associated with response to platinum and taxane therapies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5565. doi:10.1158/1538-7445.AM2014-5565