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Cancer Cell. 2016 Feb 8;29(2):159-72. doi: 10.1016/j.ccell.2016.01.002.

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.

Author information

1
Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA.
2
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4
Department of Microbiology and Immunology, Massey Cancer Center, Richmond, VA 23298, USA.
5
Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki 211-8533, Japan.
6
Department of Pediatrics, Children's Hospital of Richmond, VCU, Richmond, VA 23298, USA.
7
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
8
Cancer Genome Project, The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
9
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
10
Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Perkinson Building, Richmond, VA 23298, USA. Electronic address: acfaber@vcu.edu.

Abstract

Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.

PMID:
26859456
PMCID:
PMC4749542
DOI:
10.1016/j.ccell.2016.01.002
[Indexed for MEDLINE]
Free PMC Article

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