EphA2 Mutation in Lung Squamous Cell Carcinoma Promotes Increased Cell Survival,Cell Invasion,Focal Adhesions,and Mammalian Target of Rapamycin Activation |
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Authors: | Leonardo Faoro Patrick A Singleton Gustavo M Cervantes Frances E Lennon Nicholas W Choong Rajani Kanteti Benjamin D Ferguson Aliya N Husain Maria S Tretiakova Nithya Ramnath Everett E Vokes Ravi Salgia |
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Institution: | From the Sections of ‡Hematology and Oncology and ;§Pulmonary and Critical Care Medicine, Department of Medicine and ;the ‖Department of Pathology.;¶Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637, and ;the **Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109 |
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Abstract: | Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130Cas. Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130Cas. WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted. |
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Keywords: | Cancer Diseases/Cancer/Oncogene Receptors/Tyrosine Kinase Signal Transduction/Protein Kinases/Tyrosine Tumor/Oncogene EphA2 Developmental Therapeutics Lung Cancer |
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