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

Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, no drugs that target MYCN have yet been developed. Here, by combining a whole genome shRNA library screen and Master Regulator Inference Algorithm (MARINa) analysis, we identified Transcription Factor Activating Protein 4 (TFAP4) as a novel synthetic lethal interactor with MYCN amplification in neuroblastoma. Silencing TFAP4 selectively inhibits MYCN amplified neuroblastoma growth both in vitro and in xenograft mice models. TFAP4 expression is inversely correlated with patient survival in MYCN-high neuroblastoma. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as seen by increased neurite outgrowth, and up-regulation of neuronal markers. TFAP4 regulates a downstream signature similar to the signature of the oncogene anaplastic lymphoma kinase (ALK). Taken together, our results validate TFAP4 as an important master regulator in MYCN amplified neuroblastoma and a novel synthetic interactor with MYCN amplification. Thus, TFAP4 may be a novel drug target for neuroblastoma treatment.