Abstract A64: Human epidermal growth factor receptor 2 (HER2) directly binds and activates focal adhesion kinase (FAK) to promote oncogenesis

• Published in: Molecular cancer therapeutics 2015-12, Vol.14 (12_Supplement_2), p.A64-A64
• Main Authors: Marlowe, Timothy, Figel, Sheila, Lenzo, Felicia, Golubovskaya, Vita, Kurenova, Elena, Tropsha, Alexander, Cance, William
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-15-A64

Introduction: Human epidermal growth factor receptor 2 (HER2) is known to require focal adhesion kinase (FAK) for cellular transformation, tumor growth, invasion, and metastasis. FAK is overexpressed in nearly all types of human cancer, serving as a molecular scaffold protein to integrate oncogenic growth factor receptors with focal adhesion proteins. We have identified a novel direct protein-protein interaction between HER2 and FAK. In this study, we investigated whether the HER2-FAK direct interaction is required for HER2-dependent oncogenesis and its potential as a novel drug target. Methods: We have taken a multidisciplinary approach (biophysics, biochemistry, molecular modeling, structural biology, and molecular biology) to map the HER2-FAK binding interface and to study the functional aspects of the interaction. Results: Our data indicated that the N-lobe of the HER2 kinase domain directly interacts with the F1 lobe of the FAK FERM domain. In addition, molecular modeling studies have identified a putative HER2-FAK interface suitable for the binding of small molecule inhibitors. Site-directed mutagenesis studies validated this binding interface. Functional data indicated that HER2 directly transphosphorylated FAK at key tyrosine residues, Y397, Y861, and Y925, irrespective of FAK kinase activity. Additionally, kinome reprogramming analysis revealed upregulation of HER2 signaling and maintenance of FAK phosphorylation after FAK-kinase inhibitor treatment. Finally, cellular data suggested that loss of the HER2-FAK interaction, but not FAK-kinase activity, resulted in a defect in Heregulin β1-stimulated cell migration/invasion. Conclusion: We have identified a direct interaction between HER2 and FAK that is required for HER2-dependent oncogenic signaling and is amenable to targeting by small molecule therapeutics. In addition, this interaction mediated a novel drug resistance mechanism whereby HER2 rescued and maintained FAK activation under FAK-kinase inhibition. Citation Format: Timothy Marlowe, Sheila Figel, Felicia Lenzo, Vita Golubovskaya, Elena Kurenova, Alexander Tropsha, William Cance. Human epidermal growth factor receptor 2 (HER2) directly binds and activates focal adhesion kinase (FAK) to promote oncogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A64.