Activation of extracellular regulated kinases (ERK1/2) but not AKT predicts poor prognosis in colorectal carcinoma and is associated with k-ras mutations

Abstract

Signal transduction and modulation represent central mechanisms in cellular processes such as cell-cycle regulation, oncogenesis, and apoptosis. The aim of this study was to determine the prognostic relevance of two kinases important in the regulation of cell proliferation and apoptosis in 135 colorectal cancer cases: AKT and extracellular regulated kinases (ERK1/2). We investigated the relationship of phospho-ERK1/2 (pERK1/2) and phospho-AKT (pAKT) with associated parameters (EGFR, COX-2, cyclin-D1), proliferative activity (Ki-67), and apoptosis (TUNEL) using immunohistochemistry. Additionally, the k-ras gene was screened for mutations to determine its putative association with ERK1/2 activation. Activation of ERK1/2 but not AKT correlated statistically with the presence of k-ras mutations (P = 0.015). Survival analysis of phospho-ERK1/2 immunoexpression showed a significant correlation with decreased overall survival (OS). The multivariate Cox regression analysis identified pERK1/2 as an independent prognostic parameter (P = 0.005). Activation of ERK1/2 in colorectal cancer may indicate aggressive tumor behavior and may constitute an independent prognostic factor. Furthermore, our data suggest that mutations of the k-ras oncogene may induce activation of ERK1/2. We propose immunohistochemical determination of pERK1/2 status as a promising candidate for the identification of high-risk patients who would benefit from new anticancer drugs targeting the ERK pathway.

AKT and ERK1/2 signaling in intrahepatic cholangiocarcinoma

“…Moreover it seems as if both kinases show different subcellular localizations in various human carcinomas. In a colon cancer study, we showed pAKT immuno-localization in the nucleus and cytoplasm [6] , in contrast to our results in ICC with a restricted immunoreactivity in the cytoplasm.…”

“…Phosphorylation of proteins either on specific tyrosine or serine residues is a posttranslational event modulating the activity of many key signaling molecules in the cell including AKT and ERK1/2 [4] . We recently demonstrated AKT and ERK phosphorylation as an independent prognostic parameter in breast cancer and colorectal cancer, respectively [5,6] . Others found an association of AKT [5,[7][8][9][10] .…”

Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY‐142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines

“…In instances of coincident activation of the RAF and PI3K pathways, combinations of AZD6244 and PI3K/mTOR inhibitors may prove efficacious. 52 It is also important to stress that ERK1/2 activation did not simply correlate with the presence of a KRAS mutation; in some cells KRAS coupled well to ERK1/2 and in others poorly and this is also seen in human tumour samples 53,54 and mouse models. 55,56 This differential coupling to downstream effectors represents a challenge and suggests that biochemical analysis should be combined with mutational profiling in interpreting patient responses and informing patient recruitment to trials.…”

Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups

“…These findings are in agreement with several larger colorectal cancer prognostic studies. 23,[32][33][34] Lymph node expression of pERK and MUC1 and loss of p16 expression also were identified as independent features of poor outcome. In particular, p16 appeared to play a more important role in predicting prognosis than any other marker, including pERK, in both primary tumors and lymph node metastases.…”