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

¹ Department of Medical Oncology, Dana-Farber Cancer Institute; ² Ludwig Center for Cancer Research at Dana-Farber/Harvard Cancer Center; Departments of ³ Radiology, ⁴ Pathology, and ⁵ Medicine, Brigham and Women's Hospital, Harvard Medical School; ⁶ Department of Pathology, Harvard Medical School, Boston, Massachusetts; and ⁷ The Broad Institute of MIT and Harvard, Cambridge, Massachusetts

Requests for reprints: Kwok-Kin Wong, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, D810, Boston, MA 02115. Phone: 617-632-6084; Fax: 617-582-7839; E-mail: kwong1{at}partners.org.

Mutations in the BRAF and KRAS genes occur in 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. [Cancer Res 2007;67(10):4933–9]

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