Abstract 753: Enhanced anti-tumor activity of erlotinib in combination with FAK tyrosine kinase inhibitors in non-small cell lung cancer

Abstract

Abstract The epidermal growth factor receptor (EGFR) is over-expressed in approximately 90% of non-small cell lung cancer (NSCLC) and as such, blockade of EGFR activity has been a primary therapeutic target for NSCLC. As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs) there is a need for additional therapeutic approaches in patients with wild-type EGFR. The extracellular matrix (ECM) has been shown to play an important role in tumor growth and response to therapy, and focal adhesion kinase (FAK) expression, a key component of signaling downstream of ECM binding to cell surface integrins, has been shown to correlate with aggressive stage in NSCLC. As the FAK-Src signaling axis can activate EGFR signaling independently of EGFR ligand-binding and kinase activity, the use of FAK tyrosine kinase inhibitors in combination with EGFR TKIs was assessed as a means of enhancing response to treatment in NSCLC. Treatment of EGFR TKI-resistant NSCLC cells (A549 and H1299 with wild-type EGFR, and H1975 with T790M acquired resistance mutation in EGFR) with FAK tyrosine kinase inhibitor PF-573,228 alone decreased cell viability. Treatment of these cell lines with a combination of PF-573,228 and the EGFR TKI erlotinib was more effective at reducing cell viability and cell migration than either treatment alone. Additionally, the growth of EGFR TKI-resistant NSCLC cells in 3-dimensional culture was significantly impaired with a combination of FAK inhibitor and erlotinib compared to either treatment alone. Interestingly, although erlotinib alone could inhibit the phosphorylation of Akt to an extent in NSCLC cell lines, the combination of erlotinib and FAK inhibitor was able to almost completely inhibit Akt phosphorylation. As persistent Akt activity is associated with lack of response to EGFR TKIs, the enhanced reduction in cell viability seen with the addition of a FAK inhibitor to treatment with erlotinib appears to be, at least in part, due to enhanced inhibition of Akt activity in these cells. The efficacy of the combination treatment was confirmed in vivo using a xenograft model with subcutaneously implanted A549 cells in nude mice. Significant inhibition of tumor growth was observed for A549-derived tumors when erlotinib was used in combination with FAK inhibitor, with some animals not yet developing palpable tumors by the end-point of the experiment. Thus, the combination of FAK inhibition with EGFR TKIs such as erlotinib results in decreased growth of NSCLC cells both in vitro and in vivo and could prove to be an effective therapeutic approach for patients with EGFR TKI-resistant NSCLC. Citation Format: Grant A. Howe, Bin Xiao, Huijun Zhao, Glenwood Goss, Christina L. Addison. Enhanced anti-tumor activity of erlotinib in combination with FAK tyrosine kinase inhibitors in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 753. doi:10.1158/1538-7445.AM2014-753