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

• DOI: 10.1016/j.ccell.2016.01.002
• Publication Date: 2016-02-08T16:53:07Z
• Authors: Jungoh Ham; Carlotta Costa; Renata Sano; Timothy L. Lochmann; Erin M. Sennott; Neha U. Patel; Anahita Dastur; Maria Gomez-Carab...; Kateryna Krytska; Aaron N. Hata; Konstantinos V. F...; Mark T. Hughes; Charles T. Jakubik; Daniel A.R. Heisey; Justin T. Ferrell; Molly L. Bristol; Ryan J. March; Craig Yates; Mark A. Hicks; Wataru Nakajima; Madhu Gowda; Brad E. Windle; Mikhail G. Dozmorov; Mathew J. Garnett; Ultan McDermott; Hisashi Harada; Shirley M. Taylor; Iain M. Morgan; Cyril H. Benes; Jeffrey A. Engelman; Yael P. Mossé; Anthony C. Faber
• Keywords: N-Myc

Fewer than half of children with high-risk neuroblastoma survive. Many these tumors harbor high-level amplification MYCN, which correlates 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 paradoxical, MYCN-driven upregulation NOXA. Screening for enhancers ABT-199 neuroblastomas, demonstrate Aurora Kinase A MLN8237 combines induce widespread apoptosis. In diverse models neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, multiple instances led complete regression.