Focal Adhesion Kinase (FAK) is a 125 kDa tyrosine kinase that is localized to contact points between cells and their extracellular matrix. We have demonstrated that FAK overexpression and upregulation occurred in early stages of tumorigenesis. We have also shown that FAK overexpression suppresses apoptosis, thus providing a survival signal to human cancer cells. Furthermore, our data has recently shown that the amino-terminus of FAK can induce apoptosis in breast cancer cells and can bind to a death domain containing serine-threonine kinase, Receptor Interacting Protein, (RIP). In addition, we have identified peptides that bind to the carboxy-terminus of FAK and cause apoptosis. 1 of these peptides contained a sequence homologous to the vascular endothelial growth receptor 3 (VEGFR-3) protein that we have shown to bind FAK. This proposal focuses on the biology of FAK in the development of cancer and on the biological mechanism by which attenuation of amino-terminal and carboxy-terminal FAK signaling causes tumor cell apoptosis. The first specific aim is to define the critical components of the amino terminus of FAK (FAKNT) that are responsible for its pro-apoptotic properties. We will define the portion(s) of FAK-NT that induce loss of adhesion in breast cancer cells and bind to RIP. Next, we will perform functional analyses of different peptides that bind the carboxy-terminus of FAK (FAK-CD), inhibit FAK function, and induce apoptosis in breast cancer cells. We will define their biological effects in different tumor cell lines to determine if they can induce apoptosis, perform initial binding studies using NMR spectroscopy, and perform site directed mutagenesis to determine which amino acids are critical for interaction with FAK-CD. Finally, we will define the physical interaction between FAK and VEGFR-3, determine the mechanism of survival signaling mediated by this interaction, and examine the relationship between levels of expression of FAK and VEGFR-3 in translational studies of primary human breast cancers. By defining the mechanism of interaction between FAK and its critical binding partners, we will identify novel sites for molecular targeting to induce apoptosis in human breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA065910-09
Application #
6988808
Study Section
Special Emphasis Panel (ZRG1-ONC-U (03))
Program Officer
Sussman, Daniel J
Project Start
1996-09-30
Project End
2010-04-30
Budget Start
2005-07-15
Budget End
2006-04-30
Support Year
9
Fiscal Year
2005
Total Cost
$309,188
Indirect Cost
Name
University of Florida
Department
Surgery
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Zhang, Hao; Shao, Huanjie; Golubovskaya, Vita M et al. (2016) Efficacy of focal adhesion kinase inhibition in non-small cell lung cancer with oncogenically activated MAPK pathways. Br J Cancer 115:203-11
Wilton, John; Kurenova, Elena; Pitzonka, Laura et al. (2016) Pharmacokinetic analysis of the FAK scaffold inhibitor C4 in dogs. Eur J Drug Metab Pharmacokinet 41:55-67
Marlowe, Timothy A; Lenzo, Felicia L; Figel, Sheila A et al. (2016) Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors. Mol Cancer Ther 15:3028-3039
Stewart, Jerry E; Ma, Xiaojie; Megison, Michael et al. (2015) Inhibition of FAK and VEGFR-3 binding decreases tumorigenicity in neuroblastoma. Mol Carcinog 54:9-23
Golubovskaya, Vita; Curtin, Leslie; Groman, Adrienne et al. (2015) In vivo toxicity, metabolism and pharmacokinetic properties of FAK inhibitor 14 or Y15 (1, 2, 4, 5-benzenetetramine tetrahydrochloride). Arch Toxicol 89:1095-101
Golubovskaya, Vita M; Sumbler, Brittany; Ho, Baotran et al. (2014) MiR-138 and MiR-135 directly target focal adhesion kinase, inhibit cell invasion, and increase sensitivity to chemotherapy in cancer cells. Anticancer Agents Med Chem 14:18-28
Gogate, Priyanka N; Ethirajan, Manivannan; Kurenova, Elena V et al. (2014) Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK-VEGFR3 protein-protein interaction. Eur J Med Chem 80:154-166
Kurenova, Elena; Ucar, Deniz; Liao, Jianqun et al. (2014) A FAK scaffold inhibitor disrupts FAK and VEGFR-3 signaling and blocks melanoma growth by targeting both tumor and endothelial cells. Cell Cycle 13:2542-53
Golubovskaya, Vita M; Ho, Baotran; Conroy, Jeffrey et al. (2014) Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex. Cancers (Basel) 6:166-78
Dy, Grace K; Ylagan, Lourdes; Pokharel, Saraswati et al. (2014) The prognostic significance of focal adhesion kinase expression in stage I non-small-cell lung cancer. J Thorac Oncol 9:1278-84

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