Oncotarget

Research Papers:

Unique roles of Akt1 and Akt2 in IGF-IR mediated lung tumorigenesis

Elizabeth S. Franks, Ritesh Briah, Robert A. Jones and Roger A. Moorehead _

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Oncotarget. 2016; 7:3297-3316. https://doi.org/10.18632/oncotarget.6489

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Abstract

S. Elizabeth Franks1, Ritesh Briah1, Robert A. Jones1, Roger A. Moorehead1

1Department of Biomedical Science, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada

Correspondence to:

Roger A. Moorehead, e-mail: rmoorehe@uoguelph.ca

Keywords: Akt, lung cancer, IGF-IR, transgenic mice, tumor development

Received: July 27, 2015     Accepted: November 16, 2015     Published: December 07, 2015

ABSTRACT

AKT is a serine-threonine kinase that becomes hyperactivated in a number of cancers including lung cancer. Based on AKT's association with malignancy, molecules targeting AKT have entered clinical trials for solid tumors including lung cancer. However, the AKT inhibitors being evaluated in clinical trials indiscriminately inhibit all three AKT isoforms (AKT1–3) and it remains unclear whether AKT isoforms have overlapping or divergent functions. Using a transgenic mouse model where IGF-IR overexpression drives lung tumorigenesis, we found that loss of Akt1 inhibited while loss of Akt2 enhanced lung tumor development. Lung tumors that developed in the absence of Akt2 were less likely to appear as discrete nodules and more frequently displayed a dispersed growth pattern. RNA sequencing revealed a number of genes differentially expressed in lung tumors lacking Akt2 and five of these genes, Actc1, Bpifa1, Mmp2, Ntrk2, and Scgb3a2 have been implicated in human lung cancer. Using 2 human lung cancer cell lines, we observed that a selective AKT1 inhibitor, A-674563, was a more potent regulator of cell survival than the pan-AKT inhibitor, MK-2206. This study suggests that compounds selectively targeting AKT1 may prove more effective than compounds that inhibit all three AKT isoforms at least in the treatment of lung adenocarcinoma.


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