Mechanisms of action and resistance in histone methylation-targeted therapy

Makoto Yamagishi (), Yuta Kuze, Seiichiro Kobayashi, Makoto Nakashima, Satoko Morishima, Toyotaka Kawamata, Junya Makiyama, Kako Suzuki, Masahide Seki, Kazumi Abe, Kiyomi Imamura, Eri Watanabe, Kazumi Tsuchiya, Isao Yasumatsu, Gensuke Takayama, Yoshiyuki Hizukuri, Kazumi Ito, Yukihiro Taira, Yasuhito Nannya, Arinobu Tojo, Toshiki Watanabe, Shinji Tsutsumi, Yutaka Suzuki () and Kaoru Uchimaru ()
Additional contact information
Makoto Yamagishi: The University of Tokyo
Yuta Kuze: The University of Tokyo
Seiichiro Kobayashi: The University of Tokyo
Makoto Nakashima: The University of Tokyo
Satoko Morishima: University of the Ryukyus
Toyotaka Kawamata: The University of Tokyo
Junya Makiyama: The University of Tokyo
Kako Suzuki: The University of Tokyo
Masahide Seki: The University of Tokyo
Kazumi Abe: The University of Tokyo
Kiyomi Imamura: The University of Tokyo
Eri Watanabe: The University of Tokyo
Kazumi Tsuchiya: The University of Tokyo
Isao Yasumatsu: Daiichi Sankyo RD Novare
Gensuke Takayama: Daiichi Sankyo
Yoshiyuki Hizukuri: Daiichi Sankyo
Kazumi Ito: Daiichi Sankyo
Yukihiro Taira: The University of Tokyo
Yasuhito Nannya: The University of Tokyo
Arinobu Tojo: Tokyo Medical and Dental University
Toshiki Watanabe: St Marianna University
Shinji Tsutsumi: Daiichi Sankyo
Yutaka Suzuki: The University of Tokyo
Kaoru Uchimaru: The University of Tokyo

Nature, 2024, vol. 627, issue 8002, 221-228

Abstract: Abstract Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1–7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1–EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2–compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.

Date: 2024
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DOI: 10.1038/s41586-024-07103-x

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