title: Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors.
abstract: Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development. We therefore sought to determine if these two drugs have additive effects in PCa models. The effect of both agents, singly and in combination was evaluated in a variety of PCa cell lines in vitro and in vivo. All cell lines tested responded to both drugs with decreased invasion, soft agar colony formation and growth in vivo, with additive effects seen with combination treatment. Activation of the FGFR, AKT, ERK and STAT3 pathways was examined in treated cells. AZD5363 inhibited AKT signaling and increased FGFR1 signaling, which partially compensated for decreased AKT kinase activity. While AZD4547 could effectively block the ERK pathway, combination treatment was needed to completely block STAT3 activation. Thus combination treatment with AKT and FGFR kinase inhibitors have additive effects on malignant phenotypes in vitro and in vivo by inhibiting multiple signaling pathways and mitigating the compensatory upregulation of FGFR signaling induced by AKT kinase inhibition. Our studies suggest that co-targeting these pathways may be efficacious in advanced PCa.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Department of Veterans Affairs Medical Center Baylor College of Medicine, Houston, 77030, TX, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Department of Veterans Affairs Medical Center Baylor College of Medicine, Houston, 77030, TX, USA.
authors.forename: Longjiang
authors.initials: L
authors.lastname: Shao
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Department of Veterans Affairs Medical Center Baylor College of Medicine, Houston, 77030, TX, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Castro
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Department of Veterans Affairs Medical Center Baylor College of Medicine, Houston, 77030, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D016513:Mice, SCID; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C575618:capivasertib
keywords: AKT; fibroblast growth factors; kinase inhibitor; prostate cancer; signal transduction