Profiling of phospho-AKT, phospho-mTOR, phospho-MAPK and EGFR in non-small cell lung cancer.
Activation of numerous pathways has been documented in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) has emerged as a common therapeutic target. The mitogen-activated protein kinase (MAPK) and AKT signaling pathways are downstream of EGFR and deregulated via genetic and epigenetic mechanisms in many human cancers. We evaluated selected markers in the EGFR pathway with reference to outcome. Tissues from 220 cases of NSCLC patients presented in a tissue microarray were assayed with immunohistochemistry for phosphorylated AKT, phosphorylated MAPK, phosphorylated mTOR, and EGFR and then quantified by automated image analysis. Individually, the biomarkers did not predict. Combined as ratios, p-mTOR/p-AKT, and p-MAPK/EGFR function as prognostic markers of survival (p=0.008 and p=0.029, respectively), however, no significance was found after adjustment (p=0.221, p=0.103). The sum of these ratios demonstrates a stronger correlation with survival (p<0.001) and remained statistically significant after adjustment (p=0.026). The algebraic combination of biomarkers offer the capacity to understand factors that predict outcome better than current approaches of evaluating biomarkers individually or in pairs. Our results show the sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker of survival in NSCLC patients.
Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (HK, JYC, KY, CC, SMH).
Haruhisa
H
Kitano
Joon-Yong
JY
Chung
Kris
K
Ylaya
Catherine
C
Conway
Mikiko
M
Takikita
Junya
J
Fukuoka
Yoshinori
Y
Doki
Jun
J
Hanaoka
Stephen M
SM
Hewitt
D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016000:Cluster Analysis; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D015415:Biomarkers; C546842:MTOR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
AKT; EGFR; Image analysis; Immunohistochemistry; MAPK; Non-small cell lung cancer; Survival analysis; Tissue microarray; mTOR