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

Jungoh Ham,Kateryna Krytska,Hisashi Harada,Ultan Mcdermott,Wataru Nakajima,Craig Yates,Carlotta Costa,Timothy L Lochmann,Anahita Dastur,Madhu Gowda,Renata Sano,Mark Hicks ,Mikhail G Dozmorov ,Aaron N Hata ,Justin T Ferrell ,Konstantinos V Floros ,Charles T Jakubik ,Erin M Sennott ,Ryan J March ,Neha U Patel ,Mathew J Garnett ,Mark Hughes ,Iain M Morgan ,Brad E Windle ,Cyril H Benes ,María Gomez‐Caraballo ,Shirley M Taylor ,Yaël P Mossé ,Daniel A.r Heisey ,Jeffrey A Engelman ,Molly L Bristol ,Anthony C Faber

doi:10.1016/j.ccell.2016.01.002

Abstract

SummaryFewer 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.

Highlights

There are a number of successful targeted therapies that treat genetically distinct cancers
We demonstrate that the presence of MYCN amplification in neuroblastoma exhibits synthetic lethality when treated with the BCL-2 targeting agent ABT-199, and that these tumors are further sensitized by the addition of the Aurora A inhibitor, MLN8237, in cell culture models and diverse mouse models
MYCN-Amplified Neuroblastoma Cells Are Highly Sensitive to ABT-263, due to High NOXA Analysis of drug-sensitivity data of 500 solid tumor cancer cell lines from a high-throughput drug screen (Garnett et al, 2012) indicated that among all solid tumor types, neuroblastoma cell lines were exquisitely sensitive to the in-clinic BCL-2/BCL-2/xL inhibitor ABT-263 (Figure 1A)

Summary

Introduction

There are a number of successful targeted therapies that treat genetically distinct cancers (reviewed in Huang et al, 2014). Targeted therapies are being developed for a subset of neuroblastomas with ALK mutations. MYCN pathway inhibitors have proved difficult to develop. We demonstrate that the presence of MYCN amplification in neuroblastoma exhibits synthetic lethality when treated with the BCL-2 targeting agent ABT-199, and that these tumors are further sensitized by the addition of the Aurora A inhibitor, MLN8237, in cell culture models and diverse mouse models. MYCN-WT neuroblastoma cell culture models and human xenografts proved insensitive to this combination. Exploiting the paradoxical apoptosis-promoting function of MYCN amplification in neuroblastoma could be an effective strategy for the development of better therapies. ABT-199/MLN8237 combination therapy is differentially effective in the high-risk, MYCN-amplified subset of neuroblastoma

Results

Discussion

Conclusion