Combined inhibition of histone methyltransferases EZH2 and DOT1L is an effective therapy for neuroblastoma.

ABSTRACT:

Background

The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy.

Methods

We performed a high-throughput, combination chromatin-modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations.

Results

We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment

SUBMITTER: Seneviratne JA 

PROVIDER: S-EPMC11538032 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature