Potential of enhancer of zeste homolog 2 inhibitors for the treatment of SWI/SNF mutant cancers and tumor microenvironment modulation

Abstract

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), is commonly overexpressed or mutated in many cancer types, both of hematological and solid nature. Till now, plenty of EZH2 small molecule inhibitors have been developed and some of them have already been tested in clinical trials. Most of these inhibitors, however, are effective only in limited cases in the context of EZH2 gain-of-function mutated tumors such as lymphomas. Other cancer types with aberrant EZH2 expression and function require alternative approaches for successful treatment. One possibility is to exploit synthetic lethal strategy, which is based on the phenomenon that concurrent loss of two genes is detrimental but the deletion of either of them leaves cell viable. In the context of EZH2/PRC2, the most promising synthetic lethal target seems to be SWItch/Sucrose Non-Fermentable chromatin remodeling complex (SWI/SNF), which is known to counteract PRC2 functions. SWI/SNF is heavily involved in carcinogenesis and its subunits have been found mutated in approximately 20% of tumors of different kinds. In the current review, we summarize the existing knowledge of synthetic lethal relationships between EZH2/PRC2 and components of the SWI/SNF complex and discuss in detail the potential application of existing EZH2 inhibitors in cancer patients harboring mutations in SWI/SNF proteins. We also highlight recent discoveries of EZH2 involvement in tumor microenvironment regulation and consequences for future therapies. Although clinical studies are limited, the fundamental research might help to understand which patients are most likely to benefit from therapies using EZH2 inhibitors.

Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients

“…Clinical trials have also demonstrated that Tazemetostat, an oral EZH2-specific inhibitor, has a favorable safety profile and antitumor activity [ 61 , 62 , 63 , 64 ]. Studies have also indicated that combining tumor immunotherapy with epigenetic modifiers, particularly EZH2, could enhance treatment efficacy (see Reference [ 65 ] for a review). Additionally, given the efficacy of CDK4/6 inhibitors in certain types of cancers harboring SMARCA4 loss [ 66 ], we highlight that the deletion and nonsense variants in CDKN2A (p16) were found in 30% and 35% of our tumor samples, respectively.…”

Targeting super-enhancer activity for colorectal cancer therapy

“…Among components contributing to superenhancers function, the multi-protein SWI/SNF complex is most frequently mutated in up to a fourth of all cancers. SWI/SNF mutant cancers have been proposed to be sensitive to EZH2 inhibition, based on the fundamentally opposing functions of the PRC2 complex, in which EZH2 belongs, and the trithorax complex, the broader complex encompassing SWI/SNF, in suppressing and promoting transcription, respectively [115,116]. In a phase 1 trial, three of 10 patients with SWI/SNF component SMARCB1 negative malignant rhabdoid tumors and malignant epithelioid sarcomas had a partial response to the EZH2 inhibitor tazemetostat [117].…”

Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

“…EZH2 (enhancer of zeste homolog 2) is one of the most promising synthetic lethal targets identified with loss of SWI/SNF complexes [ 80 ]. EZH2, the catalytic subunit of polycomb repressive complex 2, silences gene expression through the methylation of lysine 27 on histone H3 (H3K27Me3) [ 53 ].…”