Combined inactivation of MYC and K-ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas

Phuoc T Tran, Alice C. Fan, Pavan K. Bendapudi, Shan Koh, Kim Komatsubara, Joy Chen, George Horng, David I. Bellovin, Sylvie Giuriato, Craig S. Wang, Jeffrey A. Whitsett, Dean W. Felsher

Research output: Contribution to journalArticle

Abstract

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-rasG12D oncogenes cooperate for the initiation and maintenance of tumorigeneses, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-rasG12D to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumour regression depended upon the specific tissue content. MYC-, K-rasG12D- or MYC/K-rasG12D- 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-rasG12D- induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-rasG12D resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-rasG1D in maintenance of lung tumors, we found that the down-stream mediates of K-ras G12D signaling, Stat3 and Stat5, are dephosphorylated following conditional K-rasG12D but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-rasG12D. 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.

Original languageEnglish (US)
Article numbere2125
JournalPLoS One
Volume3
Issue number5
DOIs
StatePublished - May 7 2008
Externally publishedYes

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ras Genes
oncogenes
adenocarcinoma
lymphoma
carcinogenesis
lung neoplasms
Tumors
Lymphoma
inactivation
Carcinogenesis
lungs
Oncogenes
Neoplasms
Lung
neoplasms
remission
Maintenance
genetically modified organisms
Adenocarcinoma of lung
Phosphorylation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Combined inactivation of MYC and K-ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas. / Tran, Phuoc T; Fan, Alice C.; Bendapudi, Pavan K.; Koh, Shan; Komatsubara, Kim; Chen, Joy; Horng, George; Bellovin, David I.; Giuriato, Sylvie; Wang, Craig S.; Whitsett, Jeffrey A.; Felsher, Dean W.

In: PLoS One, Vol. 3, No. 5, e2125, 07.05.2008.

Research output: Contribution to journalArticle

Tran, PT, Fan, AC, Bendapudi, PK, Koh, S, Komatsubara, K, Chen, J, Horng, G, Bellovin, DI, Giuriato, S, Wang, CS, Whitsett, JA & Felsher, DW 2008, 'Combined inactivation of MYC and K-ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas', PLoS One, vol. 3, no. 5, e2125. https://doi.org/10.1371/journal.pone.0002125
Tran, Phuoc T ; Fan, Alice C. ; Bendapudi, Pavan K. ; Koh, Shan ; Komatsubara, Kim ; Chen, Joy ; Horng, George ; Bellovin, David I. ; Giuriato, Sylvie ; Wang, Craig S. ; Whitsett, Jeffrey A. ; Felsher, Dean W. / Combined inactivation of MYC and K-ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas. In: PLoS One. 2008 ; Vol. 3, No. 5.
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AU - Tran, Phuoc T

AU - Fan, Alice C.

AU - Bendapudi, Pavan K.

AU - Koh, Shan

AU - Komatsubara, Kim

AU - Chen, Joy

AU - Horng, George

AU - Bellovin, David I.

AU - Giuriato, Sylvie

AU - Wang, Craig S.

AU - Whitsett, Jeffrey A.

AU - Felsher, Dean W.

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