EZH2 Y641F

Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.

We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability...Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

Strikingly, treating EZB cells with EZH2 inhibitor tazemetostat (taz) ex vivo reprogrammed them to re-express the full spectrum of T cell engagement genes such as ICOSL, ITGB7, 4-1BBL, and OX40L and rendered them highly immunogenic...Collectively, EZH2 inhibitors yield a potent boost to CART mediated anti-lymphoma effects by enhancing CART cell functions and B cell immunogenicity, which would likely yield a significant clinical benefit for these patients where CART cells are less active. These results prompted us to initiate a clinical trial evaluating the safety and efficacy of this combination in B cell lymphomas (NCT05934838).

Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.

In summary, XNW5004 is a potent EZH2 inhibitor with promising efficacy, pharmacokinetic and safety properties. XNW5004 is expected to be a potent therapeutic candidate in cancer treatment and is now in Phase II clinical trial for both liquid and solid tumors.

Based on the structure of EPZ6438 (1) and the binding model with PRC2, we designed a series of analogues aiming to improve the activities of EZH2 mutants...Furthermore, it showed no apparent inhibitory activity against the human ether-á-go-go related gene (hERG) (IC > 30 μM). In vivo, 29 exhibited favorable pharmacokinetic properties for oral administration and showed better efficacy than 1 in both Pfeiffer and Karpas-422 cell-mediated xenograft mouse models, indicating that it might be a new potential therapeutic candidate for EZH2 mutant cancers.

Strikingly, FDC meshwork was significantly shrank in MYC + cases, and partially restored by acquisition of Ezh2 Y641F , indicating that MYC overexpression may contribute to acquire FDC independency for the survival of lymphoma cells. Our results indicate that progression of FL critically affects the TME and acquisition of additional mutations such as MYC alters the interactions between lymphoma cells and tumor supportive immune cells in TME.

Reprogramming tumor-specific T cells to exogenously express a gain-of-function EZH2 mutant (Y641F) resulted in an enhanced ability of T cells to inhibit solid tumor growth. This work demonstrates the potential for manipulation of EZH2 in cellular therapies for solid tumors with harsh metabolic conditions and sheds light on the dynamic interplay of epigenetics and metabolic sufficiency.