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Aberrant AKT activation drives well-differentiated liposarcoma

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dc.contributor.author Marino-Enriquez, Adrian
dc.contributor.author Zhang, Yi-Xiang
dc.contributor.author Sioletic, Stefano
dc.contributor.author Kozakewich, Elena
dc.contributor.author Grebliunaite, Ruta
dc.contributor.author Ou, Wen-bin
dc.contributor.author Sicinska, Ewa
dc.contributor.author Raut, Chandrajit P.
dc.contributor.author Demetri, George D.
dc.contributor.author Perez-Atayde, Antonio R.
dc.contributor.author Wagner, Andrew J.
dc.contributor.author Fletcher, Jonathan A.
dc.contributor.author Fletcher, Christopher D. M.
dc.contributor.author Look, A. Thomas
dc.contributor.author Snyder, Eric
dc.contributor.author Gutierrez, Alejandro
dc.date.accessioned 2012-04-13T17:13:31Z
dc.date.available 2012-04-13T17:13:31Z
dc.date.issued 2011-09
dc.date.submitted 2011-04
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/1721.1/70023
dc.description This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1106127108/-/DCSupplemental. en_US
dc.description.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 zebrafish 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 heterozygotes, 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. en_US
dc.description.sponsorship Ludwig Center at Dana-Farber/Harvard Cancer Center and Harvard Medical School en_US
dc.description.sponsorship Harvard Catalyst en_US
dc.description.sponsorship National Institutes of Health (U.S.) (Award UL1 RR 025758) en_US
dc.description.sponsorship Harvard University en_US
dc.description.sponsorship National Institutes of Health (U.S.) (Grant 1K08CA133103) en_US
dc.description.sponsorship Fundación Alfonso Martín Escudero en_US
dc.language.iso en_US
dc.publisher Proceedings of the National Academy of Sciences (PNAS) en_US
dc.relation.isversionof http://dx.doi.org/10.1073/pnas.1106127108 en_US
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. en_US
dc.source PNAS en_US
dc.title Aberrant AKT activation drives well-differentiated liposarcoma en_US
dc.type Article en_US
dc.identifier.citation Gutierrez, A. et al. “Aberrant AKT Activation Drives Well-differentiated Liposarcoma.” Proceedings of the National Academy of Sciences 108.39 (2011): 16386–16391. Web. 13 Apr. 2012. en_US
dc.contributor.department David H. Koch Institute for Integrative Cancer Research at MIT en_US
dc.contributor.approver Snyder, Eric
dc.contributor.mitauthor Snyder, Eric
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Final published version en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Gutierrez, A.; Snyder, E. L.; Marino-Enriquez, A.; Zhang, Y.-X.; Sioletic, S.; Kozakewich, E.; Grebliunaite, R.; Ou, W.-b.; Sicinska, E.; Raut, C. P.; Demetri, G. D.; Perez-Atayde, A. R.; Wagner, A. J.; Fletcher, J. A.; Fletcher, C. D. M.; Look, A. T. en


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