Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors

Mi Ran Yun, Sun Min Lim, Seon Kyu Kim, Hun Mi Choi, Kyoung Ho Pyo, Seong Keun Kim, Ji Min Lee, You Won Lee, Jae Woo Choi, Hye Ryun Kim, Min Hee Hong, Keeok Haam, Nanhyung Huh, Jong Hwan Kim, Yong Sung Kim, Hyo Sup Shim, Ross Andrew Soo, Jin Yuan Shih, James Chih-Hsin Yang, Mirang KimByoung Chul Cho

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with ALK fusion-positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a panhistone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and EML4-ALK transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy. Significance: Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer.

Original languageEnglish
Pages (from-to)3350-3362
Number of pages13
JournalCancer Research
Volume78
Issue number12
DOIs
Publication statusPublished - 2018 Jun 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Yun, M. R., Lim, S. M., Kim, S. K., Choi, H. M., Pyo, K. H., Kim, S. K., Lee, J. M., Lee, Y. W., Choi, J. W., Kim, H. R., Hong, M. H., Haam, K., Huh, N., Kim, J. H., Kim, Y. S., Shim, H. S., Soo, R. A., Shih, J. Y., Chih-Hsin Yang, J., ... Cho, B. C. (2018). Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors. Cancer Research, 78(12), 3350-3362. https://doi.org/10.1158/0008-5472.CAN-17-3146