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)
First Page
4933
Last Page
4939
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.
Recommended Citation
Ji H,
Wang Z,
Perera SA,
Li D,
Liang MC,
Zaghlul S,
McNamara K,
Chen L,
Chirieac LR,
Padera R,
Bronson RT,
Thomas RK,
et a.
Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res 2007 May; 67(10):4933-9.