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DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy
Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenoty...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440127/ https://www.ncbi.nlm.nih.gov/pubmed/35999456 http://dx.doi.org/10.1038/s12276-022-00836-7 |
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author | Heo, Haejeong Kim, Jong-Hwan Lim, Hyun Jung Kim, Jeong-Hwan Kim, Miso Koh, Jaemoon Im, Joo-Young Kim, Bo-Kyung Won, Misun Park, Ji-Hwan Shin, Yang-Ji Yun, Mi Ran Cho, Byoung Chul Kim, Yong Sung Kim, Seon-Young Kim, Mirang |
author_facet | Heo, Haejeong Kim, Jong-Hwan Lim, Hyun Jung Kim, Jeong-Hwan Kim, Miso Koh, Jaemoon Im, Joo-Young Kim, Bo-Kyung Won, Misun Park, Ji-Hwan Shin, Yang-Ji Yun, Mi Ran Cho, Byoung Chul Kim, Yong Sung Kim, Seon-Young Kim, Mirang |
author_sort | Heo, Haejeong |
collection | PubMed |
description | Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenotype switching that occurs during the epithelial-to-mesenchymal transition (EMT). Although drug-induced epigenetic reprogramming is believed to alter the sensitivity of cancer cells to anticancer treatments, there is still much to learn about overcoming drug resistance. In this study, we used an in vitro model of ceritinib-resistant NSCLC and employed genome-wide DNA methylation analysis in combination with single-cell (sc) RNA-seq to identify cytidine deaminase (CDA), a pyrimidine salvage pathway enzyme, as a candidate drug target. CDA was hypomethylated and upregulated in ceritinib-resistant cells. CDA-overexpressing cells were rarely but definitively detected in the naïve cell population by scRNA-seq, and their abundance was increased in the acquired-resistance population. Knockdown of CDA had antiproliferative effects on resistant cells and reversed the EMT phenotype. Treatment with epigenome-related nucleosides such as 5-formyl-2′-deoxycytidine selectively ablated CDA-overexpressing resistant cells via accumulation of DNA damage. Collectively, our data suggest that targeting CDA metabolism using epigenome-related nucleosides represents a potential new therapeutic strategy for overcoming ALK inhibitor resistance in NSCLC. |
format | Online Article Text |
id | pubmed-9440127 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94401272022-09-16 DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy Heo, Haejeong Kim, Jong-Hwan Lim, Hyun Jung Kim, Jeong-Hwan Kim, Miso Koh, Jaemoon Im, Joo-Young Kim, Bo-Kyung Won, Misun Park, Ji-Hwan Shin, Yang-Ji Yun, Mi Ran Cho, Byoung Chul Kim, Yong Sung Kim, Seon-Young Kim, Mirang Exp Mol Med Article Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenotype switching that occurs during the epithelial-to-mesenchymal transition (EMT). Although drug-induced epigenetic reprogramming is believed to alter the sensitivity of cancer cells to anticancer treatments, there is still much to learn about overcoming drug resistance. In this study, we used an in vitro model of ceritinib-resistant NSCLC and employed genome-wide DNA methylation analysis in combination with single-cell (sc) RNA-seq to identify cytidine deaminase (CDA), a pyrimidine salvage pathway enzyme, as a candidate drug target. CDA was hypomethylated and upregulated in ceritinib-resistant cells. CDA-overexpressing cells were rarely but definitively detected in the naïve cell population by scRNA-seq, and their abundance was increased in the acquired-resistance population. Knockdown of CDA had antiproliferative effects on resistant cells and reversed the EMT phenotype. Treatment with epigenome-related nucleosides such as 5-formyl-2′-deoxycytidine selectively ablated CDA-overexpressing resistant cells via accumulation of DNA damage. Collectively, our data suggest that targeting CDA metabolism using epigenome-related nucleosides represents a potential new therapeutic strategy for overcoming ALK inhibitor resistance in NSCLC. Nature Publishing Group UK 2022-08-23 /pmc/articles/PMC9440127/ /pubmed/35999456 http://dx.doi.org/10.1038/s12276-022-00836-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Heo, Haejeong Kim, Jong-Hwan Lim, Hyun Jung Kim, Jeong-Hwan Kim, Miso Koh, Jaemoon Im, Joo-Young Kim, Bo-Kyung Won, Misun Park, Ji-Hwan Shin, Yang-Ji Yun, Mi Ran Cho, Byoung Chul Kim, Yong Sung Kim, Seon-Young Kim, Mirang DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title | DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title_full | DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title_fullStr | DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title_full_unstemmed | DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title_short | DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy |
title_sort | dna methylome and single-cell transcriptome analyses reveal cda as a potential druggable target for alk inhibitor–resistant lung cancer therapy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9440127/ https://www.ncbi.nlm.nih.gov/pubmed/35999456 http://dx.doi.org/10.1038/s12276-022-00836-7 |
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