Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2

Abstract

Inactivation of the switch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rhabdoid tumors (MRTs) or atypical teratoid rhabdoid tumors. This alteration is hypothesized to confer oncogenic dependency on EZH2 in these cancers. We report the discovery of a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activ-The compound induces apoptosis and differentiation specifically in SMARCB1-deleted MRT cells. Treatment of xenograft-bearing mice with (N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide) leads to dose-dependent regression of MRTs with correlative diminution of intratumoral trimethylation levels of lysine 27 on histone H3, and prevention of tumor regrowth after dosing cessation. These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and portend the utility of EZH2-targeted drugs for the treatment of these genetically defined cancers.epigenetic cancer therapy | EZH2 inhibitor

Chromatin proteins and modifications as drug targets

“…A subset of these tumours with inactivated SMARCB1 are thought to be dependent on the catalytic activity of EZH2 and in xenograft models, were shown to be sensitive to treatment with the potent and selective EZH2 inhibitor, EPZ6438 (Ref. 44). …”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…59 Finally, recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. 63,88 Inactivation of the chromatin remodeler SWI/SNF complex component SNF5 is highly prevalent in this disease. Targeted disruption of EZH2 also strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation.…”

“…As the administered dose of compound correlates with reduction in H3K27me3 levels in tumor tissue and of tumor growth, the clinical use of such inhibitors for cancers in which EZH2 is genetically altered is relevant. 88,89 Interestingly, Kim and colleagues discovered that EZH2 enhances STAT3 activation by trimethylating lysine180 in STAT3, and it does so preferentially in glioma stem-like cells. 90 The use of the EZH2 inhibitor 3-deazaneplanocin A (DZNep) 91,92 and a highly selective EZH2 inhibitor GSK126 93 decreases STAT3 activation in glioma stem-like cells.…”

O-GlcNAcylation regulates EZH2 protein stability and function

“…Most importantly, EZH2 overexpression in various types of cancers has been linked to oncogenesis, partly via H3K27me3 in promoters of specific tumor suppressor genes, and thus causes gene silencing (31). Targeting EZH2 is believed to be a promising strategy for cancer therapy (32,33).…”