Expression of the receptor tyrosine kinase EphA2 is increased in smokers and predicts poor survival in non-small cell lung cancer.
OBJECTIVE
Up-regulation of the receptor tyrosine kinase EphA2 has been shown in several epithelial cancers. Epidermal growth factor receptor (EGFR) and K-Ras have been reported to regulate EphA2 in several in vitro models, but this regulation has never been examined in tumors from patients. Because of the established importance of EGFR and K-Ras mutations in non-small cell lung cancer (NSCLC), we investigated the relationship between these mutations and EphA2 in this cancer type. The significance of EphA2 expression was further examined by testing for correlation with other clinical parameters.


METHODS
EphA2 expression was analyzed by immunohistochemistry in tissue microarray format using surgically resected NSCLC specimens (n = 279). EGFR and K-Ras mutation status was determined for most specimens. The correlation between EphA2 expression and EGFR or K-Ras mutation status was examined, along with several clinicopathologic variables of the tumors. The effects of increasing EGFR and K-Ras activity on EphA2 expression and activity were examined in two cell lines.


RESULTS
EphA2 expression was detected in >90% of tumor samples. Expression of EphA2 was positively correlated with activated EGFR but not with EGFR mutations. EphA2 expression was increased in patients harboring K-Ras mutations. EphA2 expression was positively correlated with a history of smoking, and high EphA2 scores predicted poorer progression-free and overall survivals.


CONCLUSIONS
EphA2 expression in NSCLC is associated with K-Ras mutations, EGFR activation, smoking history, and poor prognosis. EphA2 expression is up-regulated in the context of EGFR or K-Ras activation. The potential of EphA2 as a therapeutic target for NSCLC should be further investigated.
Brannan
Jennifer M
JM
Departments of Thoracic/Head and Neck Medical Oncology, Biostatistics, and Pathology, The University of Texas M. D. Anderson Cancer Center, USA.
Dong
Wenli
W
Prudkin
Ludmila
L
Behrens
Carmen
C
Lotan
Reuben
R
Bekele
B Nebiyou
BN
Wistuba
Ignacio
I
Johnson
Faye M
FM
D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality*; D008297:Male; D050505:Mutant Proteins / Q000502:physiology; D011379:Prognosis; D036104:Receptor, EphA2 / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology / Q000235:genetics*; D016019:Survival Analysis; D015854:Up-Regulation / Q000235:genetics
D050505:Mutant Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D036104:Receptor, EphA2