| Lung cancer is the leading cause of cancer deaths worldwide. Novel insights into the mechanism of lung tumorigenesis are required to identify the critical signaling pathways involved in cancer initiation and progression to allow subsequent development of targeted therapies. Using mouse models and analysis of human tumor samples, we have identified the DOK family genes Dok1, Dok2, and Dok3 as lung tumor suppressor genes. Single, double, and triple compound Dok1/Dok2/Dok3 knockout (KO) mice develop lung cancer with a penetrance and latency dependent on the number of lost Dok alleles, with the highest penetrance and shortest latency in the triple knockout (TKO) animals. Lung tumors from Dok KO mice are adenocarcinomas that exhibit aberrant activation of Erk and Akt signaling. Prior to tumorigenesis, Dok TKO lungs have an abnormal expansion of alveolar type II (AT2) cells and bronchioalveolar stem cells (BASCs), and activation of Erk and Akt is seen in these cellular compartments prior to frank tumorigenesis. In human lung adenocarcinoma, DOK2 is downregulated due to copy-number loss and this genetic loss is associated with EGFR and KRAS mutation in the primary tumor. Loss of DOK2 appears to be selected against in these tumors because DOK2 can suppress EGFR- and KRAS-induced lung tumorigenesis in vivo. We therefore identify DOK2 as a lung tumor suppressor gene. |
