Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors

Li, Chen; Wang, Yan; Gong, Yueqing; Zhang, Tengrui; Huang, Jiaqi; Tan, Zhen; Xue, Lixiang

doi:10.1186/s13148-021-01045-1

Cited by 51 publications

(26 citation statements)

References 87 publications

(87 reference statements)

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“…Tazemetostat and other EZH2 methyltransferase inhibitors have demonstrated efficacy and been implemented into the clinical care of hematological malignancies and sarcomas; however, they have yet to show potent activity as single agents in solid tumors 72 . Our findings provide rationale for combining EZH2 inhibitors with a senescence-inducing therapy – here produced by a MEK and CDK4/6 inhibitor combination – to promote NK and T cell-mediated eradication of senescent PDAC lesions through pro-inflammatory SASP induction.…”

Section: Discussionmentioning

confidence: 99%

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Chibaya

Murphy

Lopez-Diaz

et al. 2022

Preprint

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T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

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Section: Discussionmentioning

confidence: 99%

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Chibaya

Murphy

Lopez-Diaz

et al. 2022

Preprint

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“…Generally, chemical inhibition of EZH2 by an inhibitor will influence both tumor and immune cells in different aspects, including proliferation, apoptosis, metabolism, and cytokine as well as chemokine production. These nonspecific effects may be important barriers to the clinical application of EZH2 inhibitors ( 103 ). More research is needed to further reveal the effect, mechanism, and selectivity of different subgroups of EZH2 inhibitors on T cells.…”

Section: Discussionmentioning

confidence: 99%

Easy or Not—The Advances of EZH2 in Regulating T Cell Development, Differentiation, and Activation in Antitumor Immunity

et al. 2021

Self Cite

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Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which regulates downstream gene expression by trimethylation of lysine 27 in histone H3 (H3K27me3). EZH2 mutations or overexpressions are associated with many types of cancer. As inhibition of EZH2 activity could upregulate the expression of tumor suppressor genes, EZH2 has recently become an interesting therapeutic target for cancer therapy. Moreover, accumulating evidence has shown that EZH2 may contribute to the regulation of immune cells, especially T cells. EZH2 regulates T cell development, differentiation, and function, suggesting that EZH2 also regulates immune homeostasis in addition to tumor suppressor genes. Moreover, EZH2 can regulate T cell fate by targeting non-T cell factors such as metabolism, cytokines, and myeloid-derived suppressor cells. The role of EZH2 in this process has not been fully addressed. This review discusses up-to-date research on EZH2-mediated regulation of immunological function and the progress of immunological therapeutic strategies based on this regulation.

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“…EZH2 is overexpressed in various cancer types including castration-resistant prostate cancer and diffuse large B-cell lymphoma (DLBCL). Cancer grows as a result of EZH2 blocking CDKIs, such as p16, p21, and p27, hence accelerating cancer cell proliferation [17,18,101]. The EZH2 inhibitor GSK126 disrupts EZH2 methyltransferase activity and releases PRC2 suppression of targeted genes by competing with S-adenosylmethionine for binding to EZH2, thus causing cell quiescence.…”

Section: Gsk126 Or-s1mentioning

confidence: 99%

Advances in therapeutic agents targeting quiescent cancer cells

Nabil

Liu

et al. 2022

Acta Materia Medica

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Quiescent cancer cells (QCCs) reversibly reside in G0 phase, thus allowing them to survive chemotherapy and radiotherapy, which generally target proliferating cells. Surviving QCCs may re-proliferate, and consequently result in cancer progression, recurrence, and metastasis. Therefore, understanding the key players governing QCC survival and activation is crucial for developing QCC-targeting agents. This review presents an overview of (1) the mechanisms underlying the regulation of QCC status and (2) recent advances in the development of QCC-targeting therapeutic agents and their underlying mechanisms. The development of effective therapeutic modalities that target QCCs may enable new cancer treatments to prevent cancer progression and recurrence.

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Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors

Cited by 51 publications

References 87 publications

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Easy or Not—The Advances of EZH2 in Regulating T Cell Development, Differentiation, and Activation in Antitumor Immunity

Advances in therapeutic agents targeting quiescent cancer cells

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