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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Adenocarcinoma of Lung
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Animals
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Carcinogenesis / drug effects
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Cell Line
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / genetics*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Knockout Techniques
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Genomics
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Humans
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Lung Neoplasms / genetics*
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Lung Neoplasms / pathology
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Male
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Mice
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Mice, Transgenic
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Mutation*
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Proto-Oncogene Mas
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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ras Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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DOK2 protein, human
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MAS1 protein, human
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Phosphoproteins
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Proto-Oncogene Mas
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Tumor Suppressor Proteins
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Epidermal Growth Factor
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EGFR protein, human
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ErbB Receptors
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Extracellular Signal-Regulated MAP Kinases
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ras Proteins