Preclinical Research Shows Potential for EZH1/2 Dual Inhibitor In Relapsed/Refractory MCL


A new report on ibrutinib-resistant mantle cell lymphoma patient-derived xenograft mouse models shows the potential benefit of the EZH1/2 inhibitor OR-S1, as other similar inhibitors have shown benefit in patients with hematologic cancers.

Preclinical research suggests that enhancer zeste homologs 1 and 2 (EZH1/2) could be a potential novel target for the treatment of patients with aggressive ibrutinib‐resistant mantle cell lymphoma (MCL) via CDKN1C‐mediated cell cycle arrest, according to a report published in Cancer Science.1

Using an ibrutinib-resistant MCL patient-derived xenograft mouse model, researchers found that oral administration of the EZH1/2 inhibitor OR-S1 inhibited MCL tumor growth significantly, whereas ibrutinib did not. OR-S1 also modulated B-cell activation, differentiation, and cell cycle after looking at comprehensive gene cell expression. Analysis of in vitro growth showed that OR-S1 was also more effective than the EZH2 inhibitor GSK126.

“We identified CDKN1C (p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation,” researchers wrote in their preclinical report. The dual inhibition of EZH1/2 has proven to be a target that researchers can continue to investigate for not just patients with MCL, but other hematologic malignancies as well.

OR-S1 is considered a close analog treatment to the EZH1/2 inhibitor valemetostat (DS-3201) that had previously shown anti-tumor benefit in multiple hematological malignancies in preclinical studies.2 In a phase 1 study [NCT02732275] of valemetostat, researchers looked at 38 patients with relapsed or refractory non-Hodgkin lymphoma (NHL), which MCL is a rare subtype of. They found that among patients there was an objective response rate of 47.2% and 15 patients were able to stay on the treatment for more than 24 weeks with tumor shrinkage. This demonstrated to researchers that EZH1/2 was a viable target to continue studying in patients with NHL.

EZH1/2 are subunits of polycomb repressive complexes (PRC) of polycomb group proteins that regulate the expression of target genes. PRC are recurrently mutated or highly expressed in hematologic malignances, in particular, EZH2 is both an oncogene and tumor suppressor gene, according to Issay Kitabayashi, MD.3

High expression of EZH2 is associated with tumor aggressiveness in hematologic malignancies like MCL and can accelerate tumor growth. In a review article Kitabayashi, chief of the division of hematological malignancy, at the National Cancer Center Research Institute, Tokyo, Japan, discussed the role of OR-S1 in disrupting PRC during the growth of the tumor. Moreover, OR-S1 suppresses H3K27me3, the epigenetic modification of Histone H3, which plays a role in hematologic malignance’s growth and spread.


  1. Kagiyama Y, Fujita S, Shima Y, et al. CDKN1C-mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib. Cancer Sci. Published online March 31, 2021. doi: 10.1111/cas.14905.
  2. Morishima S, Ishitsuka K, Izutsu K, et al. First-in-Human Study of the EZH1/2 Dual Inhibitor Valemetostat in Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) - Updated Results Focusing on Adult T-Cell Leukemia-Lymphoma (ATL). Blood. 2019; 134 (suppl 1): 4025. doi: 10.1182
  3. Kitabayashi, I, Nakagawa M. Oncogenic roles of enhancer of zeste homolog 1/2 in hematological malignancies. Cancer Sci. 1028;109(8): 2342–2348. doi: 10.1111/cas.13655
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