Research ArticleCancer

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma

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Science Translational Medicine  16 May 2018:
Vol. 10, Issue 441, eaao4680
DOI: 10.1126/scitranslmed.aao4680

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A different way to differentiate neuroblastoma

Neuroblastoma is one of the more common pediatric solid tumors, and it can be difficult to treat. These tumors are characterized by the failure of neural crest precursor cells to differentiate and can sometimes be treated with compounds that induce differentiation. Unfortunately, these do not always work, and thus, Lochmann et al. performed a high-throughput drug screen in search of additional differentiating agents, particularly ones that work by altering tumor epigenetics. Through such screening, the authors identified a compound called GSK-J4, which inhibited histone demethylation, induced tumor cell differentiation, and blocked tumor growth in multiple models of neuroblastoma. In addition, GSK-J4 cooperated with two approved drugs, suggesting that it could be a valuable part of treatment for this lethal disease.

Abstract

High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)–resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity.

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