Effect of inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumor activity and bone turnover in prostate cancer (PCa) models in vivo relative to inhibition of either kinase alone.

Abstract

e15151 Background: Growth of prostate cancer (PCa) metastases relies on bidirectional interactions between the tumor and microenvironment.The Src family kinases (SFK) and insulin-like growth factor-1 receptor (IGF-1R) signaling axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are small molecule inhibitors that target SFK and IGF-1R/IR, respectively. This study examined the in vitro and in vivo effects of BMS-754807 and dasatinib on PCa growth. Methods: Antitumor effects of both reagents were tested alone and in combination in vitro in PC3 and LNCaP cells, using proliferation and apoptosis assays. Signaling pathways were interrogated by western blots. Tumor growth in vivo was assessed by orthotopic and intratibial injection of PC3 cells and subcutaneous growth of primary human xenograft PCa-133b. Serum markers were measured by ELISA. Results: In vitro, dasatinib decreased proliferation and migration of PCa cells whereas BMS-754807 induced apoptosis. All observed anti-tumor effects were enhanced when dual blockade was used. IGF-1 induced phosphorylation of Akt1, but not Akt2, was partially inhibited by either drug alone and almost completely abrogated by the combination. Dasatinib and BMS-754807 inhibited in vivo orthotopic and intratibial tumor growth of PC3 cells more potently than either as a single agent alone with a corresponding decrease in bone turnover markers. Both drugs also exhibited synergism in primary human xenograft tumors. Potent target inhibition (p-Src, p-IGF-1R, p-Akt) by the drug combination was also demonstrated in xenografts. Conclusions: The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.