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Cancer Research 67, 4933, May 15, 2007. doi: 10.1158/0008-5472.CAN-06-4592
© 2007 American Association for Cancer Research

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Experimental Therapeutics, Molecular Targets, and Chemical Biology

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

Hongbin Ji1,2, Zhenxiong Wang1, Samanthi A. Perera1, Danan Li1,2, Mei-Chih Liang1,2, Sara Zaghlul1,2, Kate McNamara1,2, Liang Chen1,2, Mitchell Albert3, Yanping Sun3, Ruqayyah Al-Hashem3, Lucian R. Chirieac4, Robert Padera4, Roderick T. Bronson6, Roman K. Thomas1,7, Levi A. Garraway1,7, Pasi A. Jänne1,5, Bruce E. Johnson1,5, Lynda Chin1 and Kwok-Kin Wong1,5

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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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Copyright © 2007 by the American Association for Cancer Research.