한빛사 논문
Haejeong Heo # 1 2, Jong-Hwan Kim # 3, Hyun Jung Lim 1 2, Jeong-Hwan Kim 1, Miso Kim 4, Jaemoon Koh 5, Joo-Young Im 1, Bo-Kyung Kim 1 2, Misun Won 1 2, Ji-Hwan Park 3, Yang-Ji Shin 1 2, Mi Ran Yun 6, Byoung Chul Cho 6, Yong Sung Kim 1 7, Seon-Young Kim # 8 9, Mirang Kim # 10 11
1Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
2Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
3Korea Bioinformation Center, KRIBB, Daejeon, 34141, Republic of Korea.
4Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
5Department of Pathology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
6Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
7Functional Genomics Institute, PDXen Biosystems Co., Daejeon, 34129, Republic of Korea.
8Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
9Korea Bioinformation Center, KRIBB, Daejeon, 34141, Republic of Korea.
10Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
11Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
#Contributed equally.
These authors contributed equally: Haejeong Heo, Jong-Hwan Kim.
These authors contributed equally: Seon-Young Kim, Mirang Kim.
Corresponding authors: Correspondence to Seon-Young Kim or Mirang Kim.
Abstract
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.
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