Oncotarget

Research Papers:

Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors

Shu Feng, Longjiang Shao, Patricia Castro, Ilsa Coleman, Peter S. Nelson, Paul D Smith, Barry R Davies and Michael Ittmann _

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Oncotarget. 2017; 8:6179-6192. https://doi.org/10.18632/oncotarget.14049

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Abstract

Shu Feng1, Longjiang Shao1, Patricia Castro1, Ilsa Coleman2, Peter S Nelson2, Paul D Smith3, Barry R Davies3, Michael Ittmann1

1Department 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

2Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

3Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, UK

Correspondence to:

Michael Ittmann, email: mittmann@bcm.edu

Keywords: prostate cancer, signal transduction, fibroblast growth factors, kinase inhibitor, AKT

Received: September 20, 2016     Accepted: December 13, 2016     Published: December 20, 2016

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.


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