Cancer Biology and Signal Transduction Phosphoproteomic Pro fi ling Identi fi es Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

Content Provider	Semantic Scholar
Author	Lee, Brian H. Y. Lin, Hui-Ming Castillo, Lesley Wu, Jianmin Raftery, Mark J. Shreeve, S. Martin Horvath, Lisa G. Daly, Roger J.
Copyright Year	2013
Abstract	Docetaxel remains the standard-of-care formen diagnosedwithmetastatic castrate-resistant prostate cancer (CRPC). However, only approximately 50% of patients benefit from treatment and all develop docetaxelresistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with docetaxel resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry–based phosphoproteomics, we identified that metastatic docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison with parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein–protein interaction networks related to these pathways in docetaxel-resistant cells. Treatmentwith the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, whereas cotreatment with PF-00562271 and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of cotreatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where coadministrationwith docetaxel may be used in patients with CRPC to overcome chemoresistance.Mol Cancer Ther; 13(1); 190–201. 2013 AACR. Introduction Prostate cancer remains the third leading cause of cancer-related death in men in the developed world (1) with castrate-resistant prostate cancer (CRPC) being the lethal stage of the disease. Docetaxel-based chemotherapy is the first-line cytotoxic treatment offering both symptomatic and survival benefits for patients diagnosed with metastatic CRPC (2, 3). However, docetaxel only clinically benefits approximately 50% of men at the cost of significant toxicity (2). Inevitably, those patients who respond develop resistance to chemotherapy. Therefore, there is an urgent need to identify novel therapeutic strategies to overcome resistance to docetaxel in patients with CRPC. Accumulating evidence has implicated several mechanisms in the development of docetaxel resistance. These include increased drug efflux through enhanced expression of multidrug resistance proteins (MDRP; 4) and perturbations in intraand intercellular signaling pathways. Examples of the latter mechanism include altered expression and/or activation of apoptotic regulators such as Clusterin (5), HSPs (6), IAPs (7), and Bcl2 (8) and components of growth factor signaling pathways, such as PI3-kinase/Akt/mTOR (9) and platelet-derived growth factor receptor (10). However, clinical trials emanating from these targets (11–16) have yet to make an impact in the clinical setting with the exception of cabazitaxel. Cabazitaxel is a novel tubulin-binding taxanewith poor affinity for the multidrug P-glycoprotein efflux pump. A randomized phase III study (TROPIC trial) demonstrated that men with CRPC progressing after Authors' Affiliations: The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst; Bioanalytical Mass Spectrometry Facility, University of New South Wales; Royal Prince Alfred Hospital, Sydney, New South Wales; Department of Biochemistry andMolecular Biology, School of Biomedical Sciences, Monash University, Melbourne, Victoria, Australia; Junior Research Group Pathoproteomics, Competence Center Functional Genomics, University of Greifswald, Greifswald,Germany; and PfizerOncology, La Jolla, California Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). L.G. Horvath and R.J. Daly contributed equally to this work. Current address for S.M. Shreeve: Janssen Pharmaceutical Companies of Johnson and Johnson, 10990 Wilshire Blvd, Suite 1200, Los Angeles, CA 90024. Corresponding Author: Roger J. Daly, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Level 1, Building 77, Monash University, VIC 3800, Australia. Telephone: 61-3-990-29301; Fax: 61-3-990-29500; E-mail: roger.daly@monash.edu doi: 10.1158/1535-7163.MCT-13-0225-T 2013 American Association for Cancer Research. Molecular Cancer Therapeutics Mol Cancer Ther; 13(1) January 2014 190 on June 21, 2017. © 2014 American Association for Cancer Research. mct.aacrjournals.org Downloaded from Published OnlineFirst November 5, 2013; DOI: 10.1158/1535-7163.MCT-13-0225-T
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