Transcriptomics

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RNA-seq of GSK-J4 Treated Neuroblastoma Cell Lines


ABSTRACT: High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential with tumors refractory to retinoic acid differentiation based therapies. Here, we leverage high-throughput drug screening of epigenetic targeted therapies across a large and diverse tumor cell line panel to uncover the hypersensitivity of neuroblastoma cells to GSK-J4, a small molecule dual inhibitor of H3K27 demethylases UTX and JMJD3. Mechanistically, GSK-J4 induced neuroblastoma differentiation and ER stress with accompanying upregulation of PUMA and apoptosis induction. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. Additionally, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Further, GSK-J4 and RA combined to induce differentiation, ER-stress and limit the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, which is the most prevalent driver gene alteration in the refractory population, PUMA induction by GSK-J4 sensitized tumors to the BCL-2 inhibitor venetoclax, demonstrating that epigenetic targeted therapies and BH3 mimetics can be rationally combined to treat 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 anti-neuroblastoma activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110709 | GEO | 2018/02/17

REPOSITORIES: GEO

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