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

Research output: Contribution to journalArticlepeer-review

152 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
Externally publishedYes

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