Title

Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.

Document Type

Article

Publication Date

2007

Keywords

Adenocarcinoma-Bronchiolo-Alveolar, Animals, Benzamides, Disease-Models-Animal, Doxycycline, Genes-ras, Lung-Neoplasms, MAP-Kinase-Kinase-1, MAP-Kinase-Kinase-2, MAP-Kinase-Signaling-System, Mice-Transgenic, Mitogen-Activated-Protein-Kinases, Mutation, Proto-Oncogene-Proteins-B-raf, Proto-Oncogene-Proteins-p21(ras)

JAX Source

Cancer Res 2007 May; 67(10):4933-9.

Abstract

Mutations in the BRAF and KRAS genes occur in approximately 1% 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. Accordingly, in vivo pharmacologic inhibition of MAPK/ERK kinase (MEK; MAPKK) using a specific MEK inhibitor, CI-1040, induced tumor regression associated with inhibition of cell proliferation and induction of apoptosis in these de novo lung tumors. CI-1040 treatment also led to dramatic tumor shrinkage in murine lung tumors driven by a mutant KRas allele. Thus, somatic mutations in different signaling intermediates of the same pathway induce exquisite dependency on a shared downstream effector. These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non-small-cell lung cancer patients.