Identifying Kinase Inhibitors as Potential Adjuvant Chemotherapeutics in Treatment for Ovarian Cancer

Abstract

In the United States, 22,000 women are diagnosed with ovarian cancer annually resulting in 14,000 deaths. This makes ovarian cancer the fifth leading cause of cancer deaths in women despite its relatively low frequency. Plasma and ascites levels of lysophosphatidic acid (LPA) are elevated in ovarian cancer patients even at early stages of the disease. LPA is a bioactive lipid involved in signal transduction. The increased LPA within the peritoneal cavity causes a cascading effect with the activation of multiple different kinase pathways in ovarian cancer cells such as the Rho‐A/Rock, Ras/MAPK, and the PI3K/Akt pathways. The activation of these kinase pathways through elevated LPA levels are known to prevent apoptosis, increase cell proliferation and metastasis, and decrease sensitivity to platinum‐based therapy. In efforts to increase the overall survival, enhance progression‐free intervals, and to improve the overall quality of life for patients with ovarian cancer, it has been hypothesized that combining traditional chemotherapeutics with kinase inhibitors would slow tumor cell proliferation and decrease disease progression. In these studies, two ovarian adenocarcinoma cell lines SKOV‐3 and CAOV‐3 are used to evaluate cell proliferation to determine IC50 values of common platinum‐based chemotherapeutics, Cisplatin, and Carboplatin, as well are the PARP inhibitors, Olaparib and Rucaparib, independently and in conjunction with of one of four kinase inhibitors; BI‐D1870 (Rsk inhibitor), MK‐2206 (Akt inhibitor), SCH772934 (Erk inhibitor), and Y27632 (Rock inhibitor). We demonstrate that the addition of kinase inhibitors to traditional and modern ovarian cancer chemotherapeutics decreases the IC50 values for these chemotherapeutics thus providing a potential pathway for improved ovarian cancer therapy.