Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas.
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.


RESULTS
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
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.
Tran
Phuoc T
PT
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, United States of America.
Fan
Alice C
AC
Bendapudi
Pavan K
PK
Koh
Shan
S
Komatsubara
Kim
K
Chen
Joy
J
Horng
George
G
Bellovin
David I
DI
Giuriato
Sylvie
S
Wang
Craig S
CS
Whitsett
Jeffrey A
JA
Felsher
Dean W
DW
D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology*; D016259:Genes, myc; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020545:Respiratory Mucosa / Q000187:drug effects
D000970:Antineoplastic Agents; D004318:Doxycycline