DOK2 inhibits EGFR-mutated lung adenocarcinoma

Berger, A. H., Chen, M., Morotti, A., Janas, J. A., Niki, M., Bronson, R. T., Taylor, B. S., Ladanyi, M., Van Aelst, L., Politi, K., Varmus, H. E., Pandolfi, P. P. (2013) DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One, 8 (11). e79526. ISSN 1932-6203

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URL: http://www.ncbi.nlm.nih.gov/pubmed/24255704
DOI: 10.1371/journal.pone.0079526

Abstract

Somatic mutations in the EGFR proto-oncogene occur in ~15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung cancer patients. Recently, we identified DOK2 as a lung adenocarcinoma tumor suppressor gene. Here we show that genomic loss of DOK2 is associated with EGFR mutations in human lung adenocarcinoma, and we hypothesized that loss of DOK2 might therefore cooperate with EGFR mutations to promote lung tumorigenesis. We tested this hypothesis using genetically engineered mouse models and find that loss of Dok2 in the mouse accelerates lung tumorigenesis initiated by oncogenic EGFR, but not that initiated by mutated Kras. Moreover, we find that DOK2 participates in a negative feedback loop that opposes mutated EGFR; EGFR mutation leads to recruitment of DOK2 to EGFR and DOK2-mediated inhibition of downstream activation of RAS. These data identify DOK2 as a tumor suppressor in EGFR-mutant lung adenocarcinoma.

Item Type: Paper
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
CSHL labs > Van Aelst lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date: 2013
Date Deposited: 18 Feb 2014 20:40
Last Modified: 04 Nov 2015 15:56
PMCID: PMC3821857
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29496

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