Effect of INPP4B loss on DNA repair and treatment strategies in ovarian cancer

Treatment options for ovarian cancer patients remain limited and overall survival is less than 50 percent despite recent clinical advances. The lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described as a tumour suppressor in the PI3K/Akt pathway with loss of expression found most pronounced in breast, ovarian cancer and melanoma. Using microarray technology a DNA repair defect was identified in INPP4B-deficient MCF-10A cells. After validation of the microarray data, I further characterised the DNA repair defect by comet assays and quantification of γH2AX, RAD51 and 53BP1 foci formation through immunofluorescence studies. Mechanistically, with collaborative efforts I discovered that INPP4B forms a protein complex with the key players of DNA repair, ATR and BRCA1, in GST pulldown and 293T overexpression assays. Finally, I assessed whether or not INPP4B loss resulted in synthetically lethal interaction with PARP inhibition, as evidenced with tumours harbouring BRCA1/2 mutations. INPP4B loss resulted in significantly increased sensitivity towards PARP inhibition, in vitro and in vivo. Given that INPP4B loss has been found in 40% of ovarian cancer patients, this study provides the rationale for establishing INPP4B as a biomarker of PARP inhibitor response, and consequently offers novel therapeutic options for a significant subset of patients