Treatment options for ovarian cancer patients remain limited and overall survival is less than 50% despite recent clinical advances. The lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) has been described as a tumor suppressor in the PI3K/Akt pathway with loss of expression found most pronounced in breast, ovarian cancer and melanoma. Using microarray technology we identified a DNA repair defect in INPP4B-deficient cells, which we further characterized by comet assays and quantification of γH2AX, RAD51 and 53BP1 foci formation. INPP4B loss resulted in significantly increased sensitivity towards PARP inhibition, comparable to loss of BRCA1 in two- and three-dimensional in vitro models, as well as in in vivo xenograft models. Mechanistically, we discovered that INPP4B forms a protein complex with the key players of DNA repair, ATR and BRCA1, in GST pulldown and 293T overexpression assays, and INPP4B loss affects BRCA1, ATM and ATR protein stability resulting in the observed DNA repair defect. 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. Loss of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) results in a DNA repair defect due to concomitant loss of BRCA1, ATR and ATM and can be therapeutically targeted with PARP inhibitors.

Previous studies showed that five miRNAs (miR-885-5p, miR-1274, miR-210-3p, miR-224 and miR-1290) were upregulated the most in clear cell renal cell carcinoma (ccRCC). Our focus was to understand from a clinical standpoint the functional consequences of upregulating miR-210-3p. Towards this, we utilized the CRISPR/Cas9 gene editing system to deplete miR-210-3p in RCC cell lines (786-o, A498 and Caki2) and characterized the outcomes. We observed that miR-210-3p depletion dramatically increased tumorigenesis, including altering the morphology of A498 and Caki2 cells in a manner characteristic of epithelial-mesenchymal transition (EMT). These results were corroborated by in vivo xenograft studies, which showed enhanced growth of tumors from miR-210-3p-depleted A498 cells. We identified Twist-related protein 1 (TWIST1) as a key target of miR-210-3p. Analysis of the ccRCC patient data in The Cancer Genome Atlas database showed a negative correlation between miR-210-3p and TWIST1 expression. High TWIST1 and low miR-210-3p expression associated with poorer overall and disease-free survival as compared to low TWIST1 and high miR-210-3p expression. These findings suggest that renal cell carcinoma progression is promoted by TWIST1 suppression mediated by miR-210-3p.