Mitochondrial Bcl-2 family dynamics define therapy response and resistance in neuroblastoma

• Type of Material: Article
• Authors: Kelly C. Goldsmith, Emory University; Michelle Gross, The Children’s Hospital of Philadelphia; Susan Peirce, Children’s Healthcare of Atlanta; Dema Luyindula, Children’s Healthcare of Atlanta; Xueyuan Liu, The Children’s Hospital of Philadelphia; Annette Vu, The Children’s Hospital of Philadelphia; Michael Sliozberg, The Children’s Hospital of Philadelphia; Rong Guo, University of Pennsylvania; Huaqing Zhao, University of Pennsylvania; C. Patrick Reynolds, Texas Tech University; Michael D. Hogarty, The Children’s Hospital of Philadelphia
• Language: English
• Date: 2012-05-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2012 American Association for Cancer Research.
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/72/10/2565
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 72
• Issue: 10
• Start Page: 2565
• End Page: 2577
• Grant/Funding Information: This work was supported by NIH CA97323, the King Family, the Richard and Sheila Sanford Chair in Pediatric Oncology, Alex’s Lemonade Stand Foundation (to M.D.H.), NIH K08-CA128925, The Cure Childhood Cancer Foundation (to K.C.G), and NIH CA82830 (to C.P.R.).
• Keywords: Bcl-2 homology proteins; mitochondrial profiling; animal models; Bcl-2 antagonist
• Research Categories: Health Sciences, Oncology

Abstract

Neuroblastoma is a childhood tumor in which transient therapeutic responses are typically followed by recurrence with lethal chemoresistant disease. In this study, we characterized the apoptotic responses in diverse neuroblastomas using an unbiased mitochondrial functional assay. We defined the apoptotic set-point of neuroblastomas using responses to distinct BH3 death domains providing a BH3 response profile, and directly confirmed survival dependencies. We found that viable neuroblastoma cells and primary tumors are primed for death with tonic sequestration of Bim, a direct activator of apoptosis, by either Bcl-2 or Mcl-1, providing a survival dependency that predicts the activity of Bcl-2 antagonists. The Bcl-2/Bcl-xL/Bcl-w inhibitor ABT-737 showed single agent activity against only Bim:Bcl-2 primed tumor xenografts. Durable complete regressions were achieved in combination with non-curative chemotherapy even for highest-risk molecular subtypes with MYCN amplification and activating ALK mutations. Furthermore, the use of unique isogenic cell lines from patients at diagnosis and at the time of relapse showed that therapy resistance was not mediated by upregulation of Bcl-2 homologues or loss of Bim priming, but by repressed Bak/Bax activation. Together, our findings provide a classification system that identifies tumors with clinical responses to Bcl-2 antagonists, defines Mcl-1 as the principal mediator of Bcl-2 antagonist resistance at diagnosis, and isolates the therapy resistant phenotype to the mitochondria.