Autophagic survival in resistance to histone deacetylase inhibitors: novel strategies to treat malignant peripheral nerve sheath tumors

摘要

Histone deactylase inhibitors (HDACis) 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 (MPNSTs), 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, SAHA, and MS-275 on a panel of human NF1-associated and sporadic MPNSTs in vitro and in vivo. A subset of MPNSTs were found to be highly sensitive to HDACis, especially to PCI-24781. All cell-lines in this group were NF1-associated. Significant pro-apoptotic 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 pharmacological 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 immune related GTPase IRGM 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.