GSK1838705A, an insulin-like growth factor-1 receptor/insulin receptor inhibitor, induces apoptosis and reduces viability of docetaxel-resistant prostate cancer cells both in vitro and in vivo

Abstract

Prostate cancer is the leading malignancy and the second most common cause of cancer-related death in men. Despite high cure rates with surgery and/or radiation, 30%-40% of patients eventually develop advanced cancer. Docetaxel is one of the most effective and well established chemotherapeutic agents for prostate cancer. However, docetaxel resistance often develops within months. Combination therapies have been proposed to improve the therapeutic efficacy of docetaxel in prostate cancer, and there is an urgent need to identify agents that are effective for treatment of the disease, especially docetaxel-resistant prostate cancer. In this work, we investigated the activity of GSK1838705A, a potent insulin-like growth factor-1 receptor (IGF1R)/insulin receptor (IR) inhibitor, in prostate cancer, especially docetaxel-resistant prostate cancer. We found that GSK1838705A could effectively reduce the viability of both docetaxel-sensitive and docetaxel-resistant prostate cancer cells. GSK1838705A induced marked apoptosis in docetaxel-resistant cells, and also dramatically inhibited migration of these cells. Further, GSK1838705A significantly inhibited phosphorylation of IGF1R/IR. Importantly, GSK1838705A significantly suppressed docetaxel-resistant PC-3R tumor growth in vivo. This is the first study of GSK1838705A in prostate cancer. Our results indicate that GSK1838705A is a promising compound for the treatment of prostate cancer, especially for those who develop resistance to docetaxel, and might shed new light on treatment for prostate cancer.