Isobutyl-Deoxynyboquinone As an Anticancer Treatment for BRCA2-Mutant Breast Cancer Cells

BRCA2 is a tumor suppressor gene involved in homologous recombination mediated DNA double-stranded break repair (Yoshida and Miki, 2004). Individuals with BRCA2 mutations have a higher risk of developing breast cancer (Kuchenbaecher et al, 2017). Interestingly, BRCA2-mutant breast tumors overexpress the enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) (Yang et al, 2014). NQO1 functions to detoxify quinones, however in the case of certain quinones they are metabolized to be cytotoxic. This bioactivation occurs through a futile redox cycle, in which NQO1 catalyzes the reduction of the quinone, which forms an unstable hydroquinone that auto-oxidizes back to the parent compound, producing reactive oxygen species (ROS). These ROS can cause DNA damage and, if left unrepaired, lead to cell death. Isobutyl-deoxynyboquinone (IB-DNQ) is an NQO1 bioactivatable quinone that potently kills NQO1+ cancer cells (Parkinson et al, 2016). However, the mechanism of IB-DNQ-mediated cell death in NQO1+ BRCA2-mutant cells has not been explored. We hypothesize that NQO1+ BRCA2-mutant cancer cells will be highly sensitive to IB-DNQ due to inherent deficits in DNA damage repair. To test this, NQO1+ BRCA2-mutant cells will be exposed to varying doses of IB-DNQ and cellular viability will be determined. In future experiments, IB-DNQ will be administered to BRCA2 wild type breast cancer cells of the same genetic background so that its potency can be compared in mutant versus non-mutant cancer cells. Since NQO1 is expressed at greater levels in BRCA2-mutant cancer cells than in non-cancerous cells, IB-DNQ may be a candidate for personalized breast cancer treatment.