Identifying Determinants of PARP Inhibitor Sensitivity in Ovarian Cancer
Technical Report,15 Sep 2015,14 Sep 2016
Institute for Cancer Research 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 BRCA1mutations 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 BRCA1mutation carriers. We hypothesized that a range of common ovarian cancer predisposing germ-line BRCA1 gene mutations produce semi-functional proteins that are capable of providing PARP inhibitor resistance. Specific Aims. 1 Identify the region of mutant BRCA1 protein critical for PARP inhibitor resistance 2 Identify genetic alterations essential for PARP inhibitor resistance 3 Determine the ability of identified genetic aberrations to serve as predictive biomarkers. We discovered that multiple truncated BRCA1 proteins are semi functional and can promote HR and chemotherapy resistance. However, when we examined BRCA1 for regions that are absolutely critical for function, we found that the retention of the coiled-coil domain and PALB2 interaction is essential for BRCA1 activity in HR and therapy resistance. Our data support the notion that loss of large regions of BRCA1 can be tolerated for DNA repair and PARPi resistance. However, loss of the BRCA1-PALB2 interaction is critical for BRCA1 protein function, HR and PARPi resistance. Additionally, we have started our work examining exome sequences and gene expression in PARPi sensitive and resistance cancer cell lines. I attended and presented my work at the Marsha Rivkin biannual Meeting in Seattle.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology