title: Aberrant AKT activation drives well-differentiated liposarcoma.
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.
authors.affiliation: Department of Pediatric Oncology, The Dana-Farber Cancer Institute, MA 02215, USA. Alejandro_Gutierrez@dfci.harvard.edu
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Eric L
authors.initials: EL
authors.lastname: Snyder
authors.forename: Adrian
authors.initials: A
authors.lastname: Marino-Enriquez
authors.forename: Yi-Xiang
authors.initials: YX
authors.lastname: Zhang
authors.forename: Stefano
authors.initials: S
authors.lastname: Sioletic
authors.forename: Elena
authors.initials: E
authors.lastname: Kozakewich
authors.forename: Ruta
authors.initials: R
authors.lastname: Grebliunaite
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Ou
authors.forename: Ewa
authors.initials: E
authors.lastname: Sicinska
authors.forename: Chandrajit P
authors.initials: CP
authors.lastname: Raut
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D004789:Enzyme Activation; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008080:Liposarcoma / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015027:Zebrafish
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human