2. Academic Validation
  3. Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

  • Cell. 2018 Sep 20;175(1):186-199.e19. doi: 10.1016/j.cell.2018.08.058.
Xun Huang 1,  Juan Yan 2,  Min Zhang 3,  Yafang Wang 1,  Yi Chen 1,  Xuhong Fu 1,  Rongrui Wei 1,  Xing-Ling Zheng 2,  Zhiwei Liu 3,  Xiong Zhang 1,  Hong Yang 1,  Bingbing Hao 4,  Yan-Yan Shen 1,  Yi Su 1,  Xiaoji Cong 3,  Min Huang 1,  Minjia Tan 5,  Jian Ding 6,  Meiyu Geng 7
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 3 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 4 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 5 Chemical Proteomics Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China. Electronic address: [email protected].
  • 6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China. Electronic address: [email protected].
  • 7 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China. Electronic address: [email protected].
PMID: 30220457 DOI: 10.1016/j.cell.2018.08.058
Abstract

Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 Inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of Cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in Cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.

Keywords

EZH2; H3K27; MAPK; MLL1; acetylation; cancer; crosstalk; histone; methylation; therapy.

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