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Lymphoma

Epigenetic therapy gains momentum

Nature Reviews Cancer volume 12, page 799 (2012)Cite this article

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inhibited growth ... of DLBCL cell lines with EZH2-activating mutations

McCabe et al. screened a library of small molecules and identified an EZH2 inhibitor, which was optimized to create GSK126, a potent S-adenosyl-methionine (SAM)-competitive inhibitor that is highly selective for EZH2 over other methyltransferases, including EZH1. GSK126 induced a reduction of H3K27me3 in DLBCL cell lines with both wild-type and mutant EZH2. Testing the compound in a panel of cell lines of different B cell lymphoma subtypes revealed that GSK126 most effectively inhibited the growth of DLBCL cells with the activating mutations Y641 or A677. This occurred through both cytostatic and cytotoxic responses, and was recapitulated by short hairpin RNAs (shRNAs) against EZH2. GSK126 and EZH2 shRNAs also led to transcriptional changes — primarily derepression of H3K27me3 targets — in DLBCL cell lines that were sensitive to GSK126. Interestingly, a muted transcriptional response and lower global H3K27me3 levels were observed in cell lines with EZH2-activating mutations that were less sensitive to GSK126, indicating that H3K27me3 levels combined with an EZH2-activating mutation might better predict response. GSK126 also inhibited the growth of established subcutaneous xenografts of two EZH2-mutant DLBCL cell lines, and significantly improved survival of the mice. Minimal side effects were observed in mice carrying xenograft tumours, and in immunocompetent mice, which is important given the roles of EZH2 in haematopoiesis and identification of loss-of-function EZH2 mutations in myeloid malignancies. Other compounds in the same chemical series as GSK126 are described by Verma et al.

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ORIGINAL RESEARCH PAPERS

  1. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem. Biol. 8, 890–896 (2012)

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  2. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 10 Oct 2012 (doi:10.1038/nature11606)

  3. Verma, S. K. et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med. Chem. Lett. 19 Oct 2012 (doi:10.1021/ml3003346)

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Authors
  1. Sarah Seton-Rogers
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Seton-Rogers, S. Epigenetic therapy gains momentum. Nat Rev Cancer 12, 799 (2012). https://doi.org/10.1038/nrc3402

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