Ip, LRH; (2016) Effect of INPP4B loss on DNA repair and treatment strategies in ovarian cancer. Doctoral thesis , UCL (University College London).

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Abstract

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.

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