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

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 10 Pg. 4933-9 (May 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17510423 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Benzamides
• Braf protein, mouse
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Map2k2 protein, mouse
• Proto-Oncogene Proteins p21(ras)
• Doxycycline

Topics

• Adenocarcinoma (enzymology, genetics, metabolism)
• Adenocarcinoma, Bronchiolo-Alveolar (enzymology, genetics, metabolism)
• Animals
• Benzamides (pharmacology)
• Disease Models, Animal
• Doxycycline (pharmacology)
• Genes, ras
• Lung Neoplasms (enzymology, genetics, metabolism)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Mutation
• Proto-Oncogene Proteins B-raf (biosynthesis, genetics)
• Proto-Oncogene Proteins p21(ras) (biosynthesis, genetics)