A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in
lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational
status and clinicopathological features
The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene
homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is
upregulated in a number of human cancers, including non-small cell lung
cancer (NSCLC). Its potential role in NSCLC progression provides an
attractive target for anticancer therapy. The expression of
phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85 alpha and
p110 gamma subunits of PI3K, phosphorylated p70S6K (p-p70S6K),
phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1
(p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens.
The results were correlated with clinicopathological features. We also
examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and
K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2
samples (p.E545K), whereas another sample displayed a rare mutation
(p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS
mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case
had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal
metastases. The expression of p-mTOR positively correlated with that of
p-AKT and p-p70S6K and was higher in adenocarcinomas along with nuclear
p110 gamma PI3K expression, whereas p-4E-BP1 expression was higher in
squamous cell carcinomas. We also established a positive association
between p85 alpha PI3K or p110 gamma PI3K and cytoplasmic p-AKT and its
downstream effectors. An inverse correlation was noted between p-4E-BP1
immunoexpression and tumour status and nuclear p-AKT expression as
regards tumour stage. Univariate survival analysis demonstrated that
p-4E-BP1 expression, either alone or in combination with cytoplasmic
p-AKT expression had an adverse prognostic significance in
adenocarcinomas. The combination of p-4E-BP1 and cytoplasmic p-AKT
expression remained significant in the multivariate analysis as a
function of their interaction with histological type. Our data
demonstrate the significance of p-4E-BP1 immunoexpression as a molecular
marker of prognostic value in adenocarcinomas, particularly when
combined with p-AKT