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

Hongbin Ji, Zhenxiong Wang, Samanthi A. Perera, Danan Li, Mei-Chih Liang, Sara Zaghlul, Kate McNamara, Liang Chen, Mitchell Albert, Yanping Sun, Ruqayyah Al-Hashem, Lucian R. Chirieac, Robert Padera, Roderick T. Bronson, Roman K. Thomas, Levi A. Garraway, Pasi A. Jänne, Bruce E. Johnson, Lynda Chin, Kwok Kin Wong*

*Corresponding author for this work

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4933-4939
Number of pages7
JournalCancer Research
Volume67
Issue number10
DOIs
StatePublished - 15 May 2007

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    Ji, H., Wang, Z., Perera, S. A., Li, D., Liang, M-C., Zaghlul, S., McNamara, K., Chen, L., Albert, M., Sun, Y., Al-Hashem, R., Chirieac, L. R., Padera, R., Bronson, R. T., Thomas, R. K., Garraway, L. A., Jänne, P. A., Johnson, B. E., Chin, L., & Wong, K. K. (2007). Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Research, 67(10), 4933-4939. https://doi.org/10.1158/0008-5472.CAN-06-4592