Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma

Shuobo Boboila,Presha Rajbhandari,Debarshi Banerjee,Jessica J Kandel,Jose M Silva,Angela Kadenhe-Chiweshe,Gonzalo Lopez,Eileen P Connolly,Andrea Califano,Jiyang Yu,Darrell J Yamashiro

doi:10.1038/s41388-018-0326-9

Abstract

Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target. We demonstrate that TFAP4 is a direct target of MYCN in neuroblastoma cells, and that its expression and activity strongly negatively correlate with neuroblastoma patient survival. Silencing TFAP4 selectively inhibits MYCN-amplified neuroblastoma cell growth both in vitro and in vivo, in xenograft mouse models. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as evidenced by increased neurite outgrowth and upregulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a key regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.

Highlights

Neuroblastoma is the most common extracranial solid tumor in childhood, accounting for 13% of all pediatric cancer mortality
We identified 396 shRNAs that were differentially expressed between the two populations (P < 0.01), of which 218 were significantly depleted in the MYCN ON population, and were MYCN synthetic lethal candidates (Fig. 1b, Supplementary Table 1)
MYCN amplification has been identified as a marker of poor prognosis for neuroblastoma, no therapeutic drug has been developed to target MYCN directly

Summary

Introduction

Neuroblastoma is the most common extracranial solid tumor in childhood, accounting for 13% of all pediatric cancer mortality. Overall survival of high-risk patients remains < 50%, despite intensive therapy with high-dose chemotherapy, surgery, stem cell transplantation, and immunotherapy [1]. Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA Despite the knowledge that MYCN amplifications represent an adverse prognostic marker, no FDA-approved or late-stage investigational compound has been developed to target MYCN directly

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Results

Conclusion