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DOK2 inhibits EGFR-mutated lung adenocarcinoma.

Publication ,  Journal Article
Berger, AH; Chen, M; Morotti, A; Janas, JA; Niki, M; Bronson, RT; Taylor, BS; Ladanyi, M; Van Aelst, L; Politi, K; Varmus, HE; Pandolfi, PP
Published in: PLoS One
2013

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.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

11

Start / End Page

e79526

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Proto-Oncogene Mas
  • Phosphoproteins
  • Mutation
  • Mice, Transgenic
  • Mice
  • Male
  • Lung Neoplasms
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Berger, A. H., Chen, M., Morotti, A., Janas, J. A., Niki, M., Bronson, R. T., … Pandolfi, P. P. (2013). DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One, 8(11), e79526. https://doi.org/10.1371/journal.pone.0079526
Berger, Alice H., Ming Chen, Alessandro Morotti, Justyna A. Janas, Masaru Niki, Roderick T. Bronson, Barry S. Taylor, et al. “DOK2 inhibits EGFR-mutated lung adenocarcinoma.PLoS One 8, no. 11 (2013): e79526. https://doi.org/10.1371/journal.pone.0079526.
Berger AH, Chen M, Morotti A, Janas JA, Niki M, Bronson RT, et al. DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One. 2013;8(11):e79526.
Berger, Alice H., et al. “DOK2 inhibits EGFR-mutated lung adenocarcinoma.PLoS One, vol. 8, no. 11, 2013, p. e79526. Pubmed, doi:10.1371/journal.pone.0079526.
Berger AH, Chen M, Morotti A, Janas JA, Niki M, Bronson RT, Taylor BS, Ladanyi M, Van Aelst L, Politi K, Varmus HE, Pandolfi PP. DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One. 2013;8(11):e79526.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

11

Start / End Page

e79526

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Proto-Oncogene Mas
  • Phosphoproteins
  • Mutation
  • Mice, Transgenic
  • Mice
  • Male
  • Lung Neoplasms
  • Humans