Comparison of different therapeutic regimens in an INI1-deficient proximal-type epithelioid sarcoma patient-derived xenograft highlights the antitumor activity of the EZH2 inhibitor EPZ-011989 and suggests autophagy as a possible cytoprotective mechanism

We report that differential gene expression analysis of epithelioid sarcoma samples removed from EPZ-011989-treated and untreated mice revealed that, among the 5521 genes with a significant differential expression (according to FDR<0.05), 62% were up-regulated and 38% down-regulated respectively, thus indicating a generally increased transcriptional activity in treated tumors, consistent with EZH2 inhibition. Interestingly, among the top 15 up-regulated genes in the EPZ-011989-treated samples, 8 are involved in cell survival pathways, including autophagy. The induction of autophagy as a fail-safe mechanism against EZH2 inhibition was further validated in the PDX-derived ES-1 cell line by evaluating the effect of autophagy inhibition on drug-induced activity. Overall design: PDX mRNA profiles of untreated and EPZ-011989 treated mice were generated by deep sequencing, in duplicate using Illumina NextSeq 500 Sequencing System