Identifying Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer
Abstract
Cells that are deficient in homologous recombination (HR) DNA repair, such as those lacking functional BRCA1 are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Ovarian cancer patients that harbored germ-line BRCA1 mutations treated with PARP inhibitors exhibited meaningful responses in early phase clinical trials. However, emerging clinical trial data indicates that PARP inhibitor therapy may benefit only a subset of BRCA1 mutation carriers. In this reporting period, we have identified genetic alterations in PARP inhibitor resistant cell lines using whole exome analyses and RNA-seq technologies. We used MDA-MB-436, HCC1395, UWB1.289 and SUM149 cell lines that all harbor BRCA1 mutations to analyze parental PARP inhibitor sensitive and resistant derivatives for gene expression and mutational changes. We identified PHC2, ARID1B, ANKLE1, CHL1 genes that had recurring mutations in PARP inhibitor resistant cell lines. In gene expression analyses, we identified PHC2, ARID1B, ANKLE1, CHL1, BST2, ASNS, EHF genes that had recurring altered expression in PARP inhibitor resistant cells. The next steps of our research will be to use siRNA to alter the expression of the genes identified and determine if they impact PARP inhibitor sensitivity and DNA repair pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2017
- Accession Number
- AD1048457
Entities
People
- Neil F. Johnson