KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer

Abstract

Phase II clinical trials of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors are ongoing and ERK1/2 activation is frequently used as a biomarker. In light of the mutational activation of BRAF and KRAS in colorectal cancer, inhibitors of the Raf-MEK-ERK mitogen-activated protein kinase are anticipated to be promising. Previous studies in pancreatic cancer have found little correlation between BRAF/KRAS mutation status and ERK1/2 activation, suggesting that identifying biomarkers of MEK inhibitor response may be more challenging than previously thought. The purpose of this study was to evaluate the effectiveness of MEK inhibitor therapy for colorectal cancer and BRAF/KRAS mutation status and ERK1/2 activation as biomarkers for MEK inhibitor therapy. First, we found that MEK inhibitor treatment impaired the anchorage-independent growth of nearly all KRAS/BRAF mutant, but not wild-type, colorectal cancer cells. There was a correlation between BRAF, but not KRAS, mutation status and ERK1/2 activation. Second, neither elevated ERK1/2 activation nor reduction of ERK1/2 activity correlated with MEK inhibition of anchorage-independent growth. Finally, we validated our cell line observations and found that ERK1/2 activation correlated with BRAF, but not KRAS, mutation status in 190 patient colorectal cancer tissues. Surprisingly, we also found that ERK activation was elevated in normal colonic epithelium, suggesting that normal cell toxicity may be a complication for colorectal cancer treatment. Our results suggest that although MEK inhibitors show promise in colorectal cancer, KRAS/BRAF mutation status, but not ERK activation as previously thought, may be useful biomarkers for MEK inhibitor sensitivity. [Mol Cancer Ther 2009;8(4):834-43]

In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer

“…3D and E). p-ERK expression was variable in this model in both vehicle-treated and PF-04691502-treated tumors, which is consistent with the findings of others that in some contexts p-ERK can be an unreliable marker of activated KRAS in tumors (20)(21)(22). To determine if these tumors exploit this pathway to limit the efficacy of PF-04691502 therapy, we next evaluated susceptibility to combined inhibition of the RAS/MAPK and PI3K pathways using the MEK inhibitor, PD-0325901, in combination with PF-04691502.…”

Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer

“…K-ras and BRAF mutations were linked with activation of AKT and ERK signaling pathway. [19][20][21][22][23][24] Therefore, the involvement of AKT and ERK activation in the increase of Bcl-2 expression can be expected in colorectal cancer. All cell lines used in this study harbored either K-ras mutation or BRAF mutation (Supplementary Figure 7a).…”

Down-regulation of CMTM8 Induces Epithelial-to-Mesenchymal Transition-like Changes via c-MET/Extracellular Signal-regulated Kinase (ERK) Signaling

“…Hepatocyte growth factor (HGF) is a mesenchymal cell-derived protein that is mitogenic for primary hepatocytes as well as other cell types (9,20,21). HGF binding to the c-MET receptor activates c-MET tyrosine kinase activity and the phosphorylation of multiple sites on the receptor.…”