Effect of dual inhibition of the Src and insulin-like growth factor-1 receptor (IGF-1R) pathways on antitumor effects in prostate cancer (PCa).
21 Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases and IGF-1R, respectively. The aim of this study was to establish antitumor co-operativity by combining IGF-1R and Src blockade in a preclinical PCa model. Methods: LNCaP and PC3 cells were used as models for androgen-dependent and independent PCa, respectively. Inhibition of Src and IGF-1R pathways was accomplished by pharmacologic agents (dasatinib against Src and BMS-754807 against IGF-1R) as well as by shRNA. Serum IGF-1 levels were measured in patients (pts) with castration-resistant PCa (CRPC) treated with dasatinib and docetaxel in a phase II trial. Results: Src inhibition decreased proliferation of PCa cells, and migration in modified Boyden Chamber and wound assays. In contrast, IGF-1R blockade induced apoptosis (increased Sub-G1 fraction cells, Annexin-V(+) cells and PARP cleavage). Phosphorylation of Akt was partially inhibited by either drug alone and almost completely abrogated by the combination. Intraprostatic injection of shIGF-1R or shSrc PC3 cells in nude mice led to an 83% and 60% decrease in tumor size compared to control shRNA, respectively. In both cell lines, all observed antitumor effects were enhanced when dual blockade was used, relative to blocking the Src or IGF-1R pathway alone. In 9/19 (47%) pts with CRPC, treatment with dasatinib resulted in a compensatory increase of serum IGF-1 levels. Conclusions: Dual inhibition of Src and IGF-1R is effective and complementary in PCa, mediated, in part, through inhibition of the downstream target Akt. In about half of pts treated with dasatinib, an increase in soluble IGF-1 levels was observed, indicating there is a compensatory upregulation of survival pathways that might be abrogated by dual inhibition of Src and IGF-1R. The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking complementary processes of tumor growth and progression. [Table: see text]