RNF25 promotes gefitinib resistance in EGFR-mutant NSCLC cells by inducing NF-κB-mediated ERK reactivation article

Jung Hee Cho, Yeon Mi You, Young Il Yeom, Dong Chul Lee, Bo Kyung Kim, Misun Won, Byoung Chul Cho, Minho Kang, Seulki Park, Suk Jin Yang, Jang Seong Kim, Jung Ae Kim, Kyung Chan Park

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Abstract

Non-small cell lung cancer (NSCLC) patients with EGFR mutations initially respond well to EGFR tyrosine kinase inhibitors (TKIs) but eventually exhibit acquired or innate resistance to the therapies typically due to gene mutations, such as EGFR T790M mutation or a second mutation in the downstream pathways of EGFR. Importantly, a significant portion of NSCLC patients shows TKI resistance without any known mechanisms, calling more comprehensive studies to reveal the underlying mechanisms. Here, we investigated a synthetic lethality with gefitinib using a genome-wide RNAi screen in TKI-resistant EGFR-mutant NSCLC cells, and identified RNF25 as a novel factor related to gefitinib resistance. Depletion of RNF25 expression substantially sensitized NSCLC cells to gefitinib treatment, while forced expression of RNF25 augmented gefitinib resistance in sensitive cells. We demonstrated that RNF25 mediates NF-κB activation in gefitinib-treated cells, which, in turn, induces reactivation of ERK signal to cause the drug resistance. We identified that the ERK reactivation occurs via the function of cytokines, such as IL-6, whose expression is transcriptionally induced in a gefitinib-dependent manner by RNF25-mediated NF-κB signals. These results suggest that RNF25 plays an essential role in gefitinib resistance of NSCLC by mediating cross-talk between NF-κB and ERK pathways, and provide a novel target for the combination therapy to overcome TKI resistance of NSCLC.

Original languageEnglish
Article number651
JournalCell Death and Disease
Volume9
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Cho, J. H., You, Y. M., Il Yeom, Y., Lee, D. C., Kim, B. K., Won, M., Cho, B. C., Kang, M., Park, S., Yang, S. J., Kim, J. S., Kim, J. A., & Park, K. C. (2018). RNF25 promotes gefitinib resistance in EGFR-mutant NSCLC cells by inducing NF-κB-mediated ERK reactivation article. Cell Death and Disease, 9(6), [651]. https://doi.org/10.1038/s41419-018-0651-5