title: Autophagic survival in resistance to histone deacetylase inhibitors: novel strategies to treat malignant peripheral nerve sheath tumors.
abstract: Histone deacetylase inhibitors (HDACi) show promise as cancer therapeutics; however, the full scope of their utility remains unknown. Here we report findings that strongly rationalize clinical evaluation of HDACis in malignant peripheral nerve sheath tumors (MPNST), a class of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur sporadically or in patients with the inherited neurofibromatosis type-1 (NF1) syndrome. We evaluated the effects of the chemical HDACis PCI-24781, suberoylanilide hydroxamic acid, and MS-275 on a panel of human NF1-associated and sporadic MPNSTs in vitro and in vivo. A subset of MPNSTs was found to be highly sensitive to HDACis, especially to PCI-24781. All cell lines in this group were NF1-associated. Significant proapoptotic effects were noted in vitro and in vivo and were independent of p53 mutational status. In contrast, as a group the sporadic-MPNST cells were markedly resistant to HDACi treatment. HDACis were found to induce productive autophagy in MPNST cells. Genetic and/or pharmacologic autophagy blockade resulted in significant HDACi-induced apoptosis in cells defined as resistant or sensitive, leading to abrogated growth of primary tumors and lung metastases in tumor xenograft assays. Among autophagy-associated genes expressed in response to HDACi, the immunity-related GTPase family, M was validated as a critical target in mediating HDACi-induced autophagy and enhanced apoptosis. Taken together, our findings strongly support the evaluation of HDACi currently in clinical trials as an important new therapeutic strategy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST.
authors.affiliation: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.forename: Keila
authors.initials: K
authors.lastname: Torres
authors.forename: Juehui
authors.initials: J
authors.lastname: Liu
authors.forename: Belinda
authors.initials: B
authors.lastname: Hernandez
authors.forename: Eric
authors.initials: E
authors.lastname: Young
authors.forename: Roman
authors.initials: R
authors.lastname: Belousov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: John M
authors.initials: JM
authors.lastname: Slopis
authors.forename: Ian E
authors.initials: IE
authors.lastname: McCutcheon
authors.forename: David
authors.initials: D
authors.lastname: McConkey
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D046529:Microscopy, Electron, Transmission; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors