Oncogenic receptor tyrosine kinases directly phosphorylate focal adhesion kinase (FAK) as a resistance mechanism to fak-kinase inhibitors

Timothy A. Marlowe, Felicia L. Lenzo, Sheila A. Figel, Abigail T. Grapes, William G. Cance

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 RTKHigh cells and (ii) the long-Term acquisition of RTKs novel to the parental cell line in RTKLow cells. 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.

Original languageEnglish (US)
Pages (from-to)3028-3039
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number12
DOIs
StatePublished - Dec 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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