title: Combined Inhibition of IGF-1R/IR and Src family kinases enhances antitumor effects in prostate cancer by decreasing activated survival pathways.
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.
  
  
  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-1-induced Akt1 phophorylation by dasatinib, whereas Akt2 phosphorylation was SFK independent and only inhibited by BMS-754807. 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.
authors.affiliation: Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Farshid
authors.initials: F
authors.lastname: Dayyani
authors.forename: Nila U
authors.initials: NU
authors.lastname: Parikh
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Varkaris
authors.forename: Jian H
authors.initials: JH
authors.lastname: Song
authors.forename: Shhyam
authors.initials: S
authors.lastname: Moorthy
authors.forename: Tanushree
authors.initials: T
authors.lastname: Chatterji
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.forename: Adam R
authors.initials: AR
authors.lastname: Wolfe
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001847:Bone Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C545990:BMS 754807; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013844:Thiazoles; D014227:Triazines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D000069439:Dasatinib