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Aberrant AKT activation drives well-differentiated liposarcoma

Alejandro Gutierrez, Eric L. Snyder, Adrian Marino-Enriquez, Yi-Xiang Zhang, Stefano Sioletic, Elena Kozakewich, Ruta Grebliunaite, Wen-bin Ou, Ewa Sicinska, Chandrajit P. Raut, George D. Demetri, Antonio R. Perez-Atayde, Andrew J. Wagner, Jonathan A. Fletcher, Christopher D. M. Fletcher and A. Thomas Look
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 39 (September 27, 2011), pp. 16386-16391
Stable URL: http://www.jstor.org/stable/41352808
Page Count: 6
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Aberrant AKT activation drives well-differentiated liposarcoma
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Abstract

Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebraf ish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 hétérozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.

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