Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate ......FAK functions as a dual kinase and scaffolding protein where it forms complexes with various oncogenic proteins such
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Running Title: Resistance to FAK-kinase Inhibitors by RTKs
Key Words: FAK inhibitors, Drug Resistance, Growth factors and receptors, Molecular modeling, Novel mechanisms. Abbreviations: Focal Adhesion Kinase (FAK), Receptor Tyrosine Kinases (RTKs), Human Epidermal Growth Factor Receptor 2 (HER2), Human Epidermal Growth Factor Receptor (EGFR), 4.1 Ezrin Radixin Moesin (FERM) Funding: This work was funded by the NCI (R01CA065910) awarded to W.G. Cance, a Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant (T32CA009072) awarded to T.A. Marlowe, and a NCI Cancer Center Support Grant for Roswell Park Cancer Institute (P30CA016056). Reprint Requests: William G. Cance, Elm & Carlton Streets, Buffalo, NY 14263 Competing interests: We declare no financial conflicts of interest. W.G. Cance is Chief Scientific Officer of FAKnostics, LLC, a company focused on FAK biomarkers and therapeutics. Word Count: 6,229 words Number of Figures: 6 Main Body Figures, 15 Supplementary Figures Number of Tables: 2 Supplementary Tables
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Acknowledgments: We would like to thank Drs. Vita Golubovskaya, Elena Kurenova, and Shelton Earp for scientific discussions regarding the research topic, Mr. Thomas Mathers for pharmaceutical industry advice, the Roswell Park Flow Cytometry Core for performing FACS analysis, and Mr. George Clinton for creative influences.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
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47. Manning BD, Cantley LC. Hitting the target: emerging technologies in the search for kinase substrates. Sci STKE. 2002;2002:pe49. 48. Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell. 2012;149:307-21. 49. Stuhlmiller TJ, Miller SM, Zawistowski JS, Nakamura K, Beltran AS, Duncan JS, et al. Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains. Cell Rep. 2015;11:390-404. 50. Kampen KR, Ter Elst A, Mahmud H, Scherpen FJ, Diks SH, Peppelenbosch MP, et al. Insights in dynamic kinome reprogramming as a consequence of MEK inhibition in MLL-rearranged AML. Leukemia. 2014;28:589-99. 51. Golubovskaya VM, Nyberg C, Zheng M, Kweh F, Magis A, Ostrov D, et al. A Small molecule Inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the Y397 site of Focal Adhesion Kinase decreases tumor growth. J Med Chem. 2008;51:7405-16.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366
Published OnlineFirst September 16, 2016.Mol Cancer Ther Timothy A. Marlowe, Felicia L. Lenzo, Sheila A. Figel, et al. FAK-kinase InhibitorsFocal Adhesion Kinase (FAK) as a Resistance Mechanism to Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 16, 2016; DOI: 10.1158/1535-7163.MCT-16-0366