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.
Highlights
EGFR and KRAS mutations are the two most frequent oncogenic events in human lung adenocarcinoma, occurring in approximately 15% and 30% of U.S lung adenocarcinoma cases, respectively [1]
To determine if DOK2 genomic loss was a feature of a specific genomic class of lung adenocarcinoma, we analyzed the relationship of DOK2 loss with mutation of EGFR or KRAS in 199 primary human lung adenocarcinomas [19,20]
Only the association with EGFR mutation was replicated in the The Cancer Genome Atlas (TCGA) data, suggesting loss of DOK2 is associated with EGFR mutation but not KRAS mutation in human lung adenocarcinoma
Summary
EGFR and KRAS mutations are the two most frequent oncogenic events in human lung adenocarcinoma, occurring in approximately 15% and 30% of U.S lung adenocarcinoma cases, respectively [1]. Somatic mutation of EGFR defines a specific subclass of lung adenocarcinomas with sensitivity to treatment with the EGFR inhibitors gefitinib or erlotinib [2,3,4]. The “downstream of tyrosine kinase” (DOK) proteins are a family of adaptor proteins that modulate tyrosine kinase signaling. Similar to the insulin receptor substrate (IRS) proteins, the seven DOK family members contain an N-terminal pleckstrin homology (PH) domain, a phospho-tyrosine binding (PTB) domain, and a C-terminus containing numerous tyrosine residues and proline-rich motifs.
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