Mutations in BRAF and KRAS Converge on Activation of the Mitogen-Activated Protein Kinase Pathway in Lung Cancer Mouse Models

Abstract

Mutations in the BRAF and KRAS genes occur in f1% to 2% and 20% to 30% of non-small-cell lung cancer patients, respectively, suggesting that the mitogen-activated protein kinase (MAPK) pathway is preferentially activated in lung cancers. Here, we show that lung-specific expression of the BRAF V600E mutant induces the activation of extracellular signal-regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung adenocarcinoma with bronchioloalveolar carcinoma features in vivo. Deinduction of transgene expression led to dramatic tumor regression, paralleled by dramatic dephosphorylation of ERK1/2, implying a dependency of BRAF-mutant lung tumors on the MAPK pathway.

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

“…Activating mutations in these MAPK‐related genes were found in many cancer types, such as breast cancer, melanoma, mesothelioma, and non‐small‐cell lung cancer, to drive the aberrant activation of ERK1/2 signaling (Davies et al ., 2002; Giltnane and Balko, 2014; Ji et al ., 2007; Kempf et al ., 2016; Millington, 2013). The deregulation of MAPK pathway represents some of the driving characteristics and key hallmarks of the cancer cell (Hanahan and Weinberg, 2000, 2011).…”

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

“…B-Raf phosphorylation leads to MEK and ERK activation. Activated ERK stimulates the transcription of genes involved in cell growth and proliferation, and apoptosis inhibition (Ji et al, 2007) (Fig. 1).…”

Bioinformatics Analysis Reveals Connection of Squamous Cell Carcinoma and Adenocarcinoma of the Lung

“…Identically, these pathways play a significant role in lung carcinomas. Mutations in the BRAF and KRAS genes occur in non-small-cell lung cancer patients, which induces the activation of extracellular signal-regulated kinase (ERK)-1/2 (MAPK) pathway and the development of lung carcinoma (Ji et al, 2007). The Wnt signaling pathway, originally identified in Drosphila melanogaster, is highly conserved in evolutionary pathways involved in homeostasis, cell proliferation, differentiation, motility, and apoptosis.…”