title: DOK2 inhibits EGFR-mutated lung adenocarcinoma.
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.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Alice H
authors.initials: AH
authors.lastname: Berger
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.forename: Justyna A
authors.initials: JA
authors.lastname: Janas
authors.forename: Masaru
authors.initials: M
authors.lastname: Niki
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.forename: Harold E
authors.initials: HE
authors.lastname: Varmus
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D002460:Cell Line; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055786:Gene Knockout Techniques; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115089:DOK2 protein, human; C000715470:MAS1 protein, human; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins