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Background  Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as “oncogene-addiction.” However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.    Methodology/Principal Findings  To examine how the MYC and  K-ras G12D   oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and  K-ras G12D   to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-,  K-ras G12D  - or MYC/ K-ras G12D  -induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas  K-ras G12D  -induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and  K-ras G12D   resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and  K-ras G12D   in maintenance of lung tumors, we found that the down-stream mediators of  K-ras G12D   signaling, Stat3 and Stat5, are dephosphorylated following conditional  K-ras G12D   but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or  K-ras G12D  . Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.    Conclusions/Significance  Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the treatment of lung cancers and lymphomas.

Combined Inactivation of MYC and K-Ras Oncogenes Reverses Tumorigenesis in Lung Adenocarcinomas and Lymphomas