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The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. EZH2 is frequently mutated and/or its expression is deregulated in various cancer types. The cancer sensitivity to inhibitors of EZH2 enzymatic activity and state-of-the-art approaches to deplete EZH2 with chemical degraders are discussed. This review also presents the clinical trials in various phases that evaluate the use of EZH2 inhibitors, both as monotherapy and in combination with other agents for the treatment of patients with diverse types of cancers. [ABSTRACT FROM AUTHOR]

Targeted therapies and immunotherapies have improved the clinical outcome of cancer patients; however, the efficacy of treatment remains frequently limited due to low predictability of response and development of drug resistance. Therefore, novel therapeutic strategies for various cancer types are needed. Current research emphasizes the potential therapeutic value of targeting WNT/β-catenin dependent signaling that is deregulated in various cancer types. Targeting the WNT/β-catenin signaling pathway with diverse synthetic and natural agents is the subject of a number of preclinical studies and clinical trials for cancer patients. The usage of nature-derived agents is attributed to their health benefits, reduced toxicity and side effects compared to synthetic agents. The review summarizes preclinical studies and ongoing clinical trials that aim to target components of the WNT/β-catenin pathway across a diverse spectrum of cancer types, highlighting their potential to improve cancer treatment. [ABSTRACT FROM AUTHOR]

Despite significant advances in targeted therapies against the hyperactivated BRAFV600/MEK pathway for patients with unresectable metastatic melanoma, acquired resistance remains an unsolved clinical problem. In this study, we focused on melanoma cells resistant to trametinib, an agent broadly used in combination therapies. Molecular and cellular changes were assessed during alternating periods of trametinib withdrawal and rechallenge in trametinib-resistant cell lines displaying either a differentiation phenotype (MITFhigh/NGFRlow) or neural crest stem-like dedifferentiation phenotype (NGFRhigh/MITFlow). Neither drug withdrawal nor drug rechallenge induced cell death, and instead of loss of fitness, trametinib-resistant melanoma cells adapted to altered conditions by phenotype switching. In resistant cells displaying a differentiation phenotype, trametinib withdrawal markedly decreased MITF level and activity, which was associated with reduced cell proliferation capacity, and induced stemness assessed as NGFR-positive cells and senescence features, including IL-8 expression and secretion. All these changes could be reversed by trametinib re-exposure, which emphasizes melanoma cell plasticity. Trametinib-resistant cells displaying a dedifferentiation phenotype were less responsive presumably due to the already low level of MITF, a master regulator of the melanoma phenotype. Considering new directions of the development of anti-melanoma treatment, our study suggests that the phenotype of melanomas resistant to targeted therapy might be a crucial determinant of the selection of second-line therapy for melanoma patients. [ABSTRACT FROM AUTHOR]