Targeting DUSP activity as a treatment for high grade serous ovarian carcinoma

Abstract Identifying novel, durable treatments for high grade serous ovarian cancer (HGSOC) is paramount to extend both progression free and overall survival in patients afflicted with this disease. Dual specificity phosphatase 1 (DUSP1) was identified as one of seven genes that may significantly affect prognosis in patients with HGSOC, however the role of DUSP inhibition (DUSPi) in the treatment of HGSOC remains largely unknown. In the present study, we show that DUSP1 is highly expressed in HGSOC and confers worse progression free and overall survival. Further, we corroborate data that show DUSP1 expression is directly associated with therapy resistance. Using a tissue microarray of 137 different serous ovarian carcinomas, we demonstrate the high expression of DUSP1 in primary and recurrent serous ovarian cancer. In both acquired and de novo therapy HGSOC resistant models, DUSPi both inhibited cellular proliferation and promoted cell death. Reverse phase protein array analysis of HGSOC cells revealed DUSPi led to the differential regulation of several pathways, including AMPK and mTORC. Further, in a patient-derived xenograft HGSOC model, DUSPi significantly inhibited tumor progression.