This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, J. Articles by Kurie, J. M. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Kurie, J. M.

(American Journal of Pathology. 2007;170:366-376.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060706

Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell Lines

Jie Zhang^*, Shailaja Kalyankrishna^*, Marie Wislez^*, Nishan Thilaganathan^*, Babita Saigal^*, Wei Wei, Long Ma, Ignacio I. Wistuba^*, Faye M. Johnson^* and Jonathan M. Kurie^*

From the Departments of Thoracic/Head and Neck Medical Oncology,^* Biostatistics and Applied Mathematics, and Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

The role of Src-family kinases (SFKs) in non-small cell lung cancer (NSCLC) has not been fully defined. Here we addressed this question by examining SFK phosphorylation in NSCLC biopsy samples and using genetic and pharmacological approaches to inhibit SFK expression and activity in cultured NSCLC cells. Immunohistochemical analysis of NSCLC biopsy samples using a Tyr416 phosphorylation-specific, pan-SFK antibody revealed staining in 123 (33%) of 370 tumors. Because c-Src is known to be both an upstream activator and downstream mediator of epidermal growth factor receptor (EGFR), we next investigated SFK phosphorylation in a panel of NSCLC cell lines, including ones that depend on EGFR for survival. The EGFR-dependent NSCLC cell lines HCC827 and H3255 had increased phosphorylation of SFKs, and treatment of these cells with an SFK inhibitor (PP1 or SKI-606) induced apoptosis. PP1 decreased phosphorylation of EGFR, ErbB2, and ErbB3 and strikingly enhanced apoptosis by gefitinib, an EGFR inhibitor. HCC827 cells transfected with c-Src short hairpin RNA exhibited diminished phosphorylation of EGFR and ErbB2 and decreased sensitivity to apoptosis by PP1 or gefitinib. We conclude that SFKs are activated in NSCLC biopsy samples, promote the survival of EGFR-dependent NSCLC cells, and should be investigated as therapeutic targets in NSCLC patients.

This article has been cited by other articles:

				A. J. VanMeter, A. S. Rodriguez, E. D. Bowman, J. Jen, C. C. Harris, J. Deng, V. S. Calvert, A. Silvestri, C. Fredolini, V. Chandhoke, et al. Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer: Differential Epidermal Growth Factor Receptor (EGPR) Phosphorylation Events Associated with Mutated EGFR Compared with Wild Type Mol. Cell. Proteomics, October 1, 2008; 7(10): 1902 - 1924. [Abstract] [Full Text] [PDF]

				J. Zhang, K. Iwanaga, K. C. Choi, M. Wislez, M. G. Raso, W. Wei, I. I. Wistuba, and J. M. Kurie Intratumoral Epiregulin Is a Marker of Advanced Disease in Non-Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells Cancer Prevention Research, August 1, 2008; 1(3): 201 - 207. [Abstract] [Full Text] [PDF]

				G. Giaccone and P. A. Zucali Src as a potential therapeutic target in non-small-cell lung cancer Ann. Onc., July 1, 2008; 19(7): 1219 - 1223. [Abstract] [Full Text] [PDF]