Format

Send to

Choose Destination
Cancer Cell. 2012 Aug 14;22(2):222-34. doi: 10.1016/j.ccr.2012.06.014.

Therapeutic effect of γ-secretase inhibition in KrasG12V-driven non-small cell lung carcinoma by derepression of DUSP1 and inhibition of ERK.

Author information

1
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
2
Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
3
Bioinformatics Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
4
Comparative Pathology Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
5
Molecular Imaging Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
6
Confocal Microscopy Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
7
Tumor Markers Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
8
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
9
Cancer Epigenetics and Biology Program - IDIBELL, Barcelona, Spain.
#
Contributed equally

Abstract

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.

PMID:
22897852
PMCID:
PMC3813920
DOI:
10.1016/j.ccr.2012.06.014
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Secondary source ID, Grant support

Publication type

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center