Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK.
Here, we have investigated the role of the Notch pathway in the generation and maintenance of Kras(G12V)-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and RBPJ are essential for the formation of NSCLCs. Of importance, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and reduced phosphorylated ERK without changes in phosphorylated MEK. Mechanistically, we show that HES1 directly binds to and represses the promoter of DUSP1, encoding a dual phosphatase that is active against phospho-ERK. Accordingly, GSI treatment upregulates DUSP1 and decreases phospho-ERK. These data provide proof of the in vivo therapeutic potential of GSIs in primary NSCLCs.
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Antonio
A
Maraver
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Pablo J
PJ
Fernández-Marcos
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.|Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
Daniel
D
Herranz
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Maribel
M
Muñoz-Martin
Bioinformatics Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Gonzalo
G
Gomez-Lopez
Comparative Pathology Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Marta
M
Cañamero
Molecular Imaging Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Francisca
F
Mulero
Confocal Microscopy Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Diego
D
Megías
Tumor Markers Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Marta
M
Sanchez-Carbayo
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Jie
J
Shen
Cancer Epigenetics and Biology Program - IDIBELL, Barcelona, Spain.
Montserrat
M
Sanchez-Cespedes
Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
Teresa
T
Palomero
Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
Adolfo
A
Ferrando
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Manuel
M
Serrano
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072056:Transcription Factor HES-1; D016896:Treatment Outcome; D018631:ras Proteins / Q000378:metabolism*
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D018398:Homeodomain Proteins; D050505:Mutant Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D018631:ras Proteins; C489734:Hes1 protein, mouse; C095101:Psen2 protein, mouse; C078493:HES1 protein, human; C517019:DUSP1 protein, human; C517020:Dusp1 protein, mouse