Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors.

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 pan-histone 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. Cancer Res; 78(12); 3350-62. ©2018 AACR.

• Authors: 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, Byoung Chul Cho
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 12 Pg. 3350-3362 (06 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29669761 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• EML4-ALK fusion protein, human
• Histone Deacetylase Inhibitors
• Histones
• MIRN34 microRNA, human
• MIRN449 microRNA, human
• MicroRNAs
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Pyrimidines
• Sulfones
• Panobinostat
• ALK protein, human
• Anaplastic Lymphoma Kinase
• ceritinib

Topics

• Acetylation (drug effects)
• Anaplastic Lymphoma Kinase (antagonists & inhibitors, genetics, metabolism)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Enhancer Elements, Genetic (genetics)
• Epigenesis, Genetic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histones (genetics)
• Humans
• Lung (pathology)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, SCID
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics)
• Panobinostat (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Sulfones (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays