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 Kim & 1 others ByoungChul Cho

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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

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MicroRNAs
Epigenomics
Drug Resistance
Lung Neoplasms
anaplastic lymphoma kinase
Neoplasms
Mutation
Acetylation
Transcriptome
Heterografts
Histones
Transgenic Mice
Transcriptional Activation
Lysine
Messenger RNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yun, Mi Ran ; Lim, Sun Min ; Kim, Seon Kyu ; Choi, Hun Mi ; Pyo, Kyoung Ho ; Kim, Seong Keun ; Lee, Ji Min ; Lee, You Won ; Choi, Jae Woo ; Kim, Hye Ryun ; Hong, Min Hee ; Haam, Keeok ; Huh, Nanhyung ; Kim, Jong Hwan ; Kim, Yong Sung ; Shim, Hyo Sup ; Soo, Ross Andrew ; Shih, Jin Yuan ; Chih-Hsin Yang, James ; Kim, Mirang ; Cho, ByoungChul. / Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors. In: Cancer Research. 2018 ; Vol. 78, No. 12. pp. 3350-3362.
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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.",
author = "Yun, {Mi Ran} and Lim, {Sun Min} and Kim, {Seon Kyu} and Choi, {Hun Mi} and Pyo, {Kyoung Ho} and Kim, {Seong Keun} and Lee, {Ji Min} and Lee, {You Won} and Choi, {Jae Woo} and Kim, {Hye Ryun} and Hong, {Min Hee} and Keeok Haam and Nanhyung Huh and Kim, {Jong Hwan} and Kim, {Yong Sung} and Shim, {Hyo Sup} and Soo, {Ross Andrew} and Shih, {Jin Yuan} and {Chih-Hsin Yang}, James and Mirang Kim and ByoungChul Cho",
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Yun, MR, Lim, SM, Kim, SK, Choi, HM, Pyo, KH, Kim, SK, Lee, JM, Lee, YW, Choi, JW, Kim, HR, Hong, MH, Haam, K, Huh, N, Kim, JH, Kim, YS, Shim, HS, Soo, RA, Shih, JY, Chih-Hsin Yang, J, Kim, M & Cho, B 2018, 'Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors', Cancer Research, vol. 78, no. 12, pp. 3350-3362. https://doi.org/10.1158/0008-5472.CAN-17-3146

Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors. / Yun, Mi Ran; Lim, Sun Min; Kim, Seon Kyu; Choi, Hun Mi; Pyo, Kyoung Ho; Kim, Seong Keun; Lee, Ji Min; Lee, You Won; Choi, Jae Woo; Kim, Hye Ryun; Hong, Min Hee; Haam, Keeok; Huh, Nanhyung; Kim, Jong Hwan; Kim, Yong Sung; Shim, Hyo Sup; Soo, Ross Andrew; Shih, Jin Yuan; Chih-Hsin Yang, James; Kim, Mirang; Cho, ByoungChul.

In: Cancer Research, Vol. 78, No. 12, 15.06.2018, p. 3350-3362.

Research output: Contribution to journalArticle

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T1 - Enhancer remodeling and MicroRNA alterations are associated with acquired resistance to ALK inhibitors

AU - Yun, Mi Ran

AU - Lim, Sun Min

AU - Kim, Seon Kyu

AU - Choi, Hun Mi

AU - Pyo, Kyoung Ho

AU - Kim, Seong Keun

AU - Lee, Ji Min

AU - Lee, You Won

AU - Choi, Jae Woo

AU - Kim, Hye Ryun

AU - Hong, Min Hee

AU - Haam, Keeok

AU - Huh, Nanhyung

AU - Kim, Jong Hwan

AU - Kim, Yong Sung

AU - Shim, Hyo Sup

AU - Soo, Ross Andrew

AU - Shih, Jin Yuan

AU - Chih-Hsin Yang, James

AU - Kim, Mirang

AU - Cho, ByoungChul

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

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