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

Abstract

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.

• Authors: Yuki Kagiyama, Shuhei Fujita, Yutaka Shima, Kazutsune Yamagata, Takuo Katsumoto, Makoto Nakagawa, Daisuke Honma, Nobuaki Adachi, Kazushi Araki, Ayako Kato, Koichiro Inaki, Yoshimasa Ono, Suguru Fukuhara, Yukio Kobayashi, Kensei Tobinai, Issay Kitabayashi
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 6 Pg. 2314-2324 (Jun 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33792119 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• CDKN1C protein, human
• Cyclin-Dependent Kinase Inhibitor p57
• Piperidines
• SDC1 protein, human
• Syndecan-1
• ibrutinib
• EZH1 protein, human
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Proliferation (drug effects, genetics)
• Cyclin-Dependent Kinase Inhibitor p57 (genetics, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lymphoma, Mantle-Cell (drug therapy, genetics, pathology)
• Mice
• Piperidines (pharmacology, therapeutic use)
• Polycomb Repressive Complex 2 (antagonists & inhibitors)
• Syndecan-1 (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays