DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy

Haejeong Heo, Jong Hwan Kim, Hyun Jung Lim, Jeong Hwan Kim, Miso Kim, Jaemoon Koh, Joo Young Im, Bo Kyung Kim, Misun Won, Ji Hwan Park, Yang Ji Shin, Mi Ran Yun, Byoung Chul Cho, Yong Sung Kim, Seon Young Kim, Mirang Kim

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1236-1249
Number of pages14
JournalExperimental and Molecular Medicine
Volume54
Issue number8
DOIs
Publication statusPublished - 2022 Aug

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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