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Identifying Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer

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Technical Report,15 Sep 2016,14 Sep 2017

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The Research Institute of Fox Chase Cancer Center Philadelphia United States

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Cells that are deficient in homologous recombination HR DNA repair, such as those lacking functional BRCA1 are highly sensitive to polyADP-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.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology
  • Biochemistry

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