Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.
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.
Ji
Hongbin
H
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Wang
Zhenxiong
Z
Perera
Samanthi A
SA
Li
Danan
D
Liang
Mei-Chih
MC
Zaghlul
Sara
S
McNamara
Kate
K
Chen
Liang
L
Albert
Mitchell
M
Sun
Yanping
Y
Al-Hashem
Ruqayyah
R
Chirieac
Lucian R
LR
Padera
Robert
R
Bronson
Roderick T
RT
Thomas
Roman K
RK
Garraway
Levi A
LA
Jänne
Pasi A
PA
Johnson
Bruce E
BE
Chin
Lynda
L
Wong
Kwok-Kin
KK
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D011905:Genes, ras; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000096:biosynthesis / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D004318:Doxycycline