Reference Detail

Ref Type

Journal Article

PMID

(23620515)

Authors

Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM, Kuntz KW, Keilhack H

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	110	19	2013 May 07	7922-7	Proc Natl Acad Sci U S A

URL

Abstract Text

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 activity, (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). 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.

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Molecular Profile	Treatment Approach
SMARCB1 Q18*	EZH2 inhibitor
SMARCB1 T118Pfs*25	EZH2 inhibitor
SMARCB1 loss	EZH2 inhibitor
SMARCB1 T72Nfs*4	EZH2 inhibitor
SMARCB1 T72Qfs*13	EZH2 inhibitor
SMARCB1 del	EZH2 inhibitor
SMARCB1 L166Pfs*4	EZH2 inhibitor
SMARCB1 R53*	EZH2 inhibitor
SMARCB1 E31V	EZH2 inhibitor

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Tazemetostat	Tazemetostat	13	17

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Tazemetostat	Tazverik	EPZ6438\|E-7438\|EPZ-6438	EZH2 inhibitor 20	Tazverik (tazemetostat) binds to and inhibits EZH2, resulting in decreased tri-methylation of H3K27, and potentially leading to inhibition of cell proliferation and tumor growth (PMID: 23620515). Tazverik (tazemetostat) is FDA approved for use in patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection, and in adult patients with relapsed or refractory follicular lymphoma (R/R FL) harboring an EZH2 mutation after 2 prior therapies, and in patients with R/R FL without treatment options (FDA.gov).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
SMARCB1 loss	rhabdoid cancer	sensitive	Tazemetostat	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Tazemetostat (EPZ-6438) inhibited growth of SMARCB1-deficient malignant rhabdoid tumor cell lines in culture, and inhibited H3K27 trimethylation and induced tumor regression in a SMARCB1-deleted human malignant rhabdoid tumor cell line xenograft model (PMID: 23620515).	23620515