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Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer.
PLoS One 2016; 11(3):e0150567Plos

Abstract

Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (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. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975) were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271) both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be particularly sensitive to this combination treatment. As such, further evaluation of this combination therapy is warranted and could prove to be an effective therapeutic approach for patients with inherent EGFR TKI-resistant NSCLC.

Authors+Show Affiliations

Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Surgery, University of Ottawa, Ottawa, ON, Canada.Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.Department of Medicine, University of Ottawa, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. Department of Medicine, University of Ottawa, Ottawa, ON, Canada.Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada. Department of Medicine, University of Ottawa, Ottawa, ON, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26962872

Citation

Howe, Grant A., et al. "Focal Adhesion Kinase Inhibitors in Combination With Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer." PloS One, vol. 11, no. 3, 2016, pp. e0150567.
Howe GA, Xiao B, Zhao H, et al. Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. PLoS ONE. 2016;11(3):e0150567.
Howe, G. A., Xiao, B., Zhao, H., Al-Zahrani, K. N., Hasim, M. S., Villeneuve, J., ... Addison, C. L. (2016). Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. PloS One, 11(3), pp. e0150567. doi:10.1371/journal.pone.0150567.
Howe GA, et al. Focal Adhesion Kinase Inhibitors in Combination With Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. PLoS ONE. 2016;11(3):e0150567. PubMed PMID: 26962872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. AU - Howe,Grant A, AU - Xiao,Bin, AU - Zhao,Huijun, AU - Al-Zahrani,Khalid N, AU - Hasim,Mohamed S, AU - Villeneuve,James, AU - Sekhon,Harmanjatinder S, AU - Goss,Glenwood D, AU - Sabourin,Luc A, AU - Dimitroulakos,Jim, AU - Addison,Christina L, Y1 - 2016/03/10/ PY - 2015/09/28/received PY - 2016/02/14/accepted PY - 2016/3/11/entrez PY - 2016/3/11/pubmed PY - 2016/8/2/medline SP - e0150567 EP - e0150567 JF - PloS one JO - PLoS ONE VL - 11 IS - 3 N2 - Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (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. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975) were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271) both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be particularly sensitive to this combination treatment. As such, further evaluation of this combination therapy is warranted and could prove to be an effective therapeutic approach for patients with inherent EGFR TKI-resistant NSCLC. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26962872/Focal_Adhesion_Kinase_Inhibitors_in_Combination_with_Erlotinib_Demonstrate_Enhanced_Anti_Tumor_Activity_in_Non_Small_Cell_Lung_Cancer_ L2 - http://dx.plos.org/10.1371/journal.pone.0150567 DB - PRIME DP - Unbound Medicine ER -