1. Combined Inhibition of IGF-1R/IR and Src Family Kinases Enhances Antitumor Effects in Prostate Cancer by Decreasing Activated Survival Pathways
- Author
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Christopher J. Logothetis, Farshid Dayyani, Joan M. Carboni, Andreas Varkaris, Adam R. Wolfe, Marco M. Gottardis, Shhyam Moorthy, Tanushree Chatterji, Gary E. Gallick, Jian H. Song, Nila U. Parikh, and Sankar N. Maity
- Subjects
Male ,Mouse ,Cancer Treatment ,Dasatinib ,lcsh:Medicine ,AKT1 ,Apoptosis ,AKT2 ,Receptor, IGF Type 1 ,Mice ,Endocrinology ,0302 clinical medicine ,Molecular Cell Biology ,Tumor Cells, Cultured ,Phosphorylation ,lcsh:Science ,Insulin-like Growth Factor ,0303 health sciences ,Multidisciplinary ,Triazines ,Kinase ,Prostate Cancer ,Cell Cycle ,Animal Models ,3. Good health ,src-Family Kinases ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Drug Therapy, Combination ,Bone Diseases ,Signal transduction ,Research Article ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug ,Blotting, Western ,Mice, Nude ,Enzyme-Linked Immunosorbent Assay ,Biology ,Signaling Pathways ,03 medical and health sciences ,Model Organisms ,In vivo ,medicine ,Animals ,Humans ,Immunoprecipitation ,Protein Kinase Inhibitors ,Protein kinase B ,Cell Proliferation ,030304 developmental biology ,Endocrine Physiology ,lcsh:R ,Cancers and Neoplasms ,Prostatic Neoplasms ,Chemotherapy and Drug Treatment ,Xenograft Model Antitumor Assays ,Molecular biology ,Receptor, Insulin ,Genitourinary Tract Tumors ,Thiazoles ,Pyrimidines ,Cancer research ,Pyrazoles ,lcsh:Q ,Proto-Oncogene Proteins c-akt - Abstract
Background: Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and regulate distinct and overlapping functions in PCa progression. We examined the antitumor effects of combined inhibition of these pathways. Materials and Methods: Src andIGF-1 receptor (IGF-1R) inhibition was achieved in vitro by short hairpin (sh)RNA and in vitro and in vivo by small molecule inhibitors (dasatinib and BMS-754807, against SFK and IGF-1R/Insulin Receptor(IR), respectively). Results: In vitro, inhibition of IGF-1 signaling affected cell survival and proliferation. SFK blockade alone had modest effects on proliferation, but significantly enhanced the IGF-1R blockade. These findings correlated with a robust inhibition of IGF-1induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS754807. Thus, complete inhibition of both Akt genes, not seen by either drug alone, is likely a major mechanism for the decreased survival of PCa cells. Furthermore, dasatinib and BMS-754807 inhibited in vivo growth of the primary human xenograft MDA PCa 133, with corresponding inhibition of Akt in tumors. Also, both orthotopic and intratibial tumor growth of PC-3 cells were more potently inhibited by dual SFK and IGF-1R/IR blockade compared to either pathway alone, with a corresponding decrease in bone turnover markers. Conclusions: Dual IGF-1R/IR and SFK inhibition may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.
- Published
- 2012