Extended Data Fig. 5: Acquired EZH2 mutation in resistance to valemetostat.
From: Mechanisms of action and resistance in histone methylation-targeted therapy
a, Normalized VAF values for major somatic mutations at pre-treatment (Pre, x-axis) and recurrence (PD, y-axis) in cases with acquired PRC2 mutations (n = 5). b, Valemetostat-bound PRC2 structural models for clinically identified amino acid substitutions of EZH2 (Y111S, Y111C, Y111N, Y661N) and EED (H213R). c, Bar charts show the normalized frequency of interactions (hydrogen bonds, hydrophobic contacts, and salt-bridges) between valemetostat and wild-type or mutant PRC2 subunits over the molecular dynamics simulation time. The bar height can be greater than 100% if the protein makes more than one contact with valemetostat. d, Binding free energy changes (ΔΔG, kcal/mol) and relative affinity (%) of valemetostat to PRC2 mutants relative to wild-type PRC2 (WT) predicted by FEP+ simulation. e, H3K27me3 levels in 293 T cells expressing EZH2 and EED mutants in the presence or absence of valemetostat. Data are representative of two independent experiments. For gel source data, see Supplementary Fig. 1. f, Workflow for valemetostat outgrowth assay. g, Heatmaps represent recovered outgrowth cell numbers in TL-Om1 cells expressing PRC2 mutants in 96-well plate culture. h, Normalized EZH2 and EED RNA levels in randomly collected outgrowth clones quantified by qRT-PCR. i, Parental cells and the recovered outgrowth clones were treated with valemetostat (10 nM, 100 nM) for 7 days. Bar graphs show relative expression levels of the H3K27me3 target genes (BCL2L11 and CDKN1C).
