Reference Detail

Ref Type

Journal Article

PMID

(26552009)

Authors

Kim KH, Kim W, Howard TP, Vazquez F, Tsherniak A, Wu JN, Wang W, Haswell JR, Walensky LD, Hahn WC, Orkin SH, Roberts CW

Title

SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine	21	12	2015 Dec	1491-6	Nat Med

URL

Abstract Text

Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.

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Molecular Profile	Treatment Approach
PBRM1 Q1298*	EZH2 inhibitor
PBRM1 Q388*	EZH2 inhibitor
PBRM1 K621*	EZH2 inhibitor
PBRM1 A249fs	EZH2 inhibitor
PBRM1 K154fs	EZH2 inhibitor
PBRM1 Y106*	EZH2 inhibitor
PBRM1 R941fs	EZH2 inhibitor
PBRM1 Y331*	EZH2 inhibitor
PBRM1 Y608fs	EZH2 inhibitor
PBRM1 K135fs	EZH2 inhibitor
PBRM1 E846*	EZH2 inhibitor
PBRM1 I279Yfs*4	EZH2 inhibitor
PBRM1 G2fs	EZH2 inhibitor
PBRM1 K619fs	EZH2 inhibitor
PBRM1 E291*	EZH2 inhibitor
PBRM1 N258Kfs*6	EZH2 inhibitor
PBRM1 inact mut	EZH2 inhibitor
PBRM1 Q719*	EZH2 inhibitor
PBRM1 Q870*	EZH2 inhibitor
PBRM1 loss	EZH2 inhibitor
PBRM1 N463fs	EZH2 inhibitor
PBRM1 Q117*	EZH2 inhibitor
PBRM1 N609fs	EZH2 inhibitor
PBRM1 R58*	EZH2 inhibitor
PBRM1 R710*	EZH2 inhibitor
PBRM1 S652fs	EZH2 inhibitor

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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
PBRM1 inact mut	kidney cancer	predicted - sensitive	GSK126	Preclinical - Cell culture	Actionable	In a preclinical study, GSK126 inhibited growth of 3/4 tested renal cancer cell lines harboring PBRM1 inactivating mutations in culture, with inhibitor sensitivity associating with dependence on EZH2 catalytic activity (PMID: 26552009).	26552009