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Updated: Feb 11, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Mi Ran Yun1,2, Sun Min Lim2,3, Seon-Kyu Kim4

  • 1JE-UK Institute for Cancer Research, JEUK Co., Ltd., Gumi-City, Kyungbuk, Korea.

Cancer Research
|April 20, 2018
PubMed

Insights

Epigenetic changes, specifically altered histone acetylation and microRNA expression, drive acquired resistance to anaplastic lymphoma kinase (ALK) inhibitors in lung cancer. Targeting these epigenetic pathways may overcome resistance.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK-positive lung cancer but acquired resistance is common.
  • While secondary mutations are studied, epigenetic mechanisms in acquired resistance to ALK inhibitors are less understood.
  • Investigating dynamic transcriptome and enhancer changes during resistance development is crucial.

Purpose of the Study:

  • To explore epigenetic mechanisms, including histone acetylation and microRNA expression, in acquired resistance to ALK inhibitors.
  • To identify specific epigenetic alterations and their impact on gene expression during resistance development.
  • To evaluate therapeutic strategies targeting epigenetic pathways to overcome ALK inhibitor resistance.

Main Methods:

  • Analysis of dynamic changes in transcriptome and enhancer landscape during acquired resistance to ALK inhibitors.
  • Measurement of Histone H3 lysine 27 acetylation (H3K27ac) levels and microRNA (miRNA) expression.
  • Treatment of resistant cells, xenografts, and EML4-ALK transgenic mice with pan-histone deacetylase inhibitor (panobinostat) in combination with ALK inhibitors.
  • Paired analysis of patient samples before and after ALK inhibitor treatment.

Main Results:

  • Profound alterations in H3K27ac were observed during acquired resistance.
  • Decreased H3K27ac and miR-34a expression correlated with increased AXL activation.
  • Panobinostat reactivated tumor-suppressor miRNAs (e.g., miR-449) and synergized with ALK inhibitors.
  • Repression of miR-34a/miR-449a and AXL activation were mutually exclusive of secondary ALK mutations in patients.

Conclusions:

  • Enhancer remodeling and altered miRNA expression play significant roles in acquired resistance to ALK inhibitors.
  • Epigenetic deregulation, including H3K27ac changes and miRNA dysregulation, drives resistance in ALK-positive lung cancer.
  • Targeting epigenetic pathways, such as with pan-histone deacetylase inhibitors, offers a promising strategy to overcome acquired resistance to ALK inhibitors.

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