Abstract
Enhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.
Highlights
Enhancer of zeste homolog 2 (EZH2) is a classical epigenetic regulator of tumor genesis, metastasis, and prognosis
In current review, we summarizes the results of clinical trials using Enhancer of zeste homolog 2 inhibitors (EZH2i) and the effects of EZH2i combined with other therapeutic modalities in cancer treatment to enhance treatment efficacy compared to monotherapies
Research suggests that combination treatment with Antisense oligonucleotides (ASO) targeting EZH2 and androgen receptor (AR) transcripts has a better effect on inhibiting prostate cancer (PCa) cell growth, both in vitro and in vivo, than monotherapy with these agents [87]
Summary
Enhancer of zeste homolog 2 (EZH2) is a classical epigenetic regulator of tumor genesis, metastasis, and prognosis. SAM‐competitive inhibitor SAM-competitive EZH2i are a series of novel, highly potent small molecules that inhibit EZH2 enzyme activity. Tazemetostat Tazemetostat, the first EZH2i approved by the FDA, is a potent, selective, and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity [23] It can effectively inhibit the enzymatic activity of both wildtype EZH2 and EZH2 with catalytic domain mutation. Even 63 days after completion of EZH2i treatment, previously tumor-bearing mice remained tumor free in the two EZH2-mutant xenograft models These data portend the utility of tazemetostat as a potential treatment for these genetically defined cancers [24]. One is a first-in-human, open-label, phase I study of EZH2i in patients with relapsed or refractory B-cell NHL and advanced solid tumors. Maligant Rhabdoid Tumors, Solid Tumor, Epitheliod Sarcoma, Bladder Cancer, Prostate
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