CDKN1C‐mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib

Kagiyama, Yuki; Fujita, Shuhei; Shima, Yutaka; Yamagata, Kazuya; Katsumoto, Takuo; Nakagawa, Makoto; Honma, Daisuke; Adachi, Nobuaki; Araki, Koji; Kato, Ayako; Inaki, Koichiro; Ono, Yusuke; Fukuhara, Suguru; Kobayashi, Yukio; Tobinai, Kensei; Kitabayashi, Issay

doi:10.1111/cas.14905

Cited by 16 publications

(10 citation statements)

References 43 publications

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“…Valemetostat is a dual inhibitor of EZH1 and EZH2 that prevents trimethylation of H3K27, leading to altered gene expression patterns, which suppresses proliferation of EZH1/2-dependent cancer cells. Compared with established EZH2-specific inhibitors (GSK126), dual EZH1 and EZH2 inhibitors showed a significantly stronger reduction in H3K27me3 levels [ 12 , 39 ]. In an ongoing open-label phase 1 study (NCT 02732275, 2 November 2020 data cut-off) evaluating valemetostat tosylate monotherapy, the objective response rate (ORR) was 55.6% in 45 relapsed/refractory (r/r) PTCL patients and 50% in 14 r/r adult T-cell leukemia/lymphoma (ATL) patients [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

et al. 2021

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T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.

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Section: Discussionmentioning

confidence: 99%

Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

et al. 2021

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“…Although GSK126 has progressed to a phase 1 clinical trial (NCT02082977), of the 22 enrolled patients with relapsed DLBCL, solid tumours, and other non-Hodgkin lymphomas, only one patient had a partial response, and seven remained stable [18]. Compared with GSK126, which inhibits only EZH2, OR-S1 is a novel dual inhibitor of EZH1 and EZH2 that fully impairs PRC2 activity and has higher anti-tumour activity than that of GSK126 in acute myeloid leukaemia, DLBCL, and mantle cell lymphoma (MCL) cells [18,19]. OR-S1 promotes quiescence in cancer cells by upregulating CDKN1C, which encodes p57 and blocks Rb phosphorylation.…”

Section: Gsk126 Or-s1mentioning

confidence: 99%

“…After treatment of mice bearing MCL patient-derived xenografts with the new MCL drug ibrutinib, the tumour size has been found to reach nearly 40,000 mm 3 . Although one study has found that OR-S1 suppresses almost 90% of tumour growth, the treated mice survived only until study completion [19]. Despite its potential to induce quiescence in cancer cells and its in vivo tolerability, OR-S1 has yet to be clinically tested.…”

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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“…Kagiyama et al assessed the effect of a novel EZH1/2 dual inhibitor, named OR-S1, a close analog of valemetostat, also known as DS-3201 or (R)-OR-S2, on MCL tumor growth (139).…”

Section: Valemetostatmentioning

confidence: 99%

The Status and Prospects of Epigenetics in the Treatment of Lymphoma

Liu

et al. 2022

Front. Oncol.

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The regulation of gene transcription by epigenetic modifications is closely related to many important life processes and is a hot research topic in the post-genomic era. Since the emergence of international epigenetic research in the 1990s, scientists have identified a variety of chromatin-modifying enzymes and recognition factors, and have systematically investigated their three-dimensional structures, substrate specificity, and mechanisms of enzyme activity regulation. Studies of the human tumor genome have revealed the close association of epigenetic factors with various malignancies, and we have focused more on mutations in epigenetically related regulatory enzymes and regulatory recognition factors in lymphomas. A number of studies have shown that epigenetic alterations are indeed widespread in the development and progression of lymphoma and understanding these mechanisms can help guide clinical efforts. In contrast to chemotherapy which induces cytotoxicity, epigenetic therapy has the potential to affect multiple cellular processes simultaneously, by reprogramming cells to achieve a therapeutic effect in lymphoma. Epigenetic monotherapy has shown promising results in previous clinical trials, and several epigenetic agents have been approved for use in the treatment of lymphoma. In addition, epigenetic therapies in combination with chemotherapy and/or immunotherapy have been used in various clinical trials. In this review, we present several important epigenetic modalities of regulation associated with lymphoma, summarize the corresponding epigenetic drugs in lymphoma, and look at the future of epigenetic therapies in lymphoma.

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CDKN1C‐mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib

Cited by 16 publications

References 43 publications

Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

Advances in therapeutic agents targeting quiescent cancer cells

The Status and Prospects of Epigenetics in the Treatment of Lymphoma

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