title: Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors.
abstract: Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTK) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein-protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. In addition, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: (i) the rapid phosphorylation and activation of RTK signaling pathways in RTKHighcells and (ii) the long-term acquisition of RTKs novel to the parental cell line in RTKLowcells. Finally, HER2 +: cancer cells displayed resistance to FAK-kinase inhibition in 3D growth assays using a HER2 isogenic system and HER2+cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. Mol Cancer Ther; 15(12); 3028-39. ©2016 AACR.
authors.affiliation: Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Marlowe
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Lenzo
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Figel
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Abigail T
authors.initials: AT
authors.lastname: Grapes
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York. wcance@email.arizona.edu.|FAKnostics, LLC, Buffalo, New York.
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases