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Updated: Dec 30, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Enhanced JunD/RSK3 signalling due to loss of BRD4/FOXD3/miR-548d-3p axis determines BET inhibition resistance

Fang Tai1,2,3, Kunxiang Gong1,2,3, Kai Song1,2,3

  • 1Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Nature Communications
|January 16, 2020
PubMed

Insights

BET inhibitors (BETi) can kill cancer cells, but resistance is poorly understood. This study reveals that targeting the EGFR-MEK-ERK pathway can overcome resistance by restoring the BRD4/FOXD3/miR-548d-3p axis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • BET bromodomain inhibitors (BETi) show promise in cancer therapy by inducing cancer cell death.
  • Mechanisms underlying resistance to BET inhibitors are not well-defined, hindering their clinical application.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving resistance to BET inhibitors like JQ1.
  • To identify potential therapeutic strategies to overcome BET inhibitor resistance.

Main Methods:

  • Investigated the effect of JQ1 on BRD4 localization and gene expression.
  • Analyzed the role of microRNA-548d-3p (miR-548d-3p) in regulating JunD and RPS6KA2 (RSK3) expression.
  • Assessed the impact of targeting the EGFR-MEK-ERK signaling pathway on BET inhibitor resistance.

Main Results:

  • JQ1 treatment leads to BRD4 eviction from the MIR548D1 promoter, decreasing miR-548d-3p levels.
  • Reduced miR-548d-3p restores JunD expression, promoting RPS6KA2 (RSK3) transcription.
  • Activated RSK3 by ERK1/2/5 kinases confers resistance to JQ1.
  • Inhibition of MEK/ERK or EGFR signaling reverses BET inhibitor resistance.

Conclusions:

  • The BRD4/FOXD3/miR-548d-3p axis loss promotes JunD/RSK3 signaling, causing BET inhibitor resistance.
  • Targeting the EGFR-MEK-ERK pathway offers a viable strategy to overcome BET inhibitor resistance in cancer.

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