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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice

Published on: August 23, 2019

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AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition

Kai-Li Zhang1,2, Qian-Qian Shen1, Yan-Fen Fang1

  • 1Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Acta Pharmacologica Sinica
|June 8, 2019
PubMed

Insights

AZD9291, an EGFR inhibitor, disrupts Polycomb repressive complex 2 (PRC2) by inhibiting the EZH2-EED interaction. This epigenetic therapy approach downregulates EZH2 protein and mRNA, showing anti-tumor effects in breast cancer and lymphoma.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Pharmacology

Background:

  • Polycomb repressive complex 2 (PRC2) deregulation drives tumorigenesis.
  • Targeting the EZH2-EED interaction is a key epigenetic cancer therapy strategy.
  • Existing inhibitors for this interaction are limited.

Purpose of the Study:

  • To investigate AZD9291 as a potential disruptor of the EZH2-EED interaction.
  • To evaluate the anti-tumor effects of AZD9291 in breast cancer and lymphoma.
  • To elucidate the regulatory mechanisms of AZD9291 involving EZH2 and miR-34a.

Main Methods:

  • In-cell protein-protein interaction screening using NanoBRET technology.
  • Co-immunoprecipitation (Co-IP), PTSA, and CETSA assays to study PRC2 regulation.
  • MicroRNA array, luciferase reporter assays, and qRT-PCR to analyze molecular interactions.

Main Results:

  • AZD9291, an EGFR inhibitor, disrupts the EZH2-EED interaction, impairing PRC2 activity.
  • AZD9291 treatment leads to EZH2 protein downregulation.
  • AZD9291 upregulates miR-34a, which in turn downregulates EZH2 mRNA expression.

Conclusions:

  • AZD9291 shows potential as a lead compound for developing PRC2 protein-protein interaction antagonists.
  • EZH2 mRNA may be a direct target of miR-34a via non-canonical base pairing.
  • AZD9291 exhibits anti-tumor effects in breast cancer and diffuse large B-cell lymphoma models.
Keywords:
AZD9291EZH2–EEDPRC2miR-34anon-canonical base pairing

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