Long non-coding RNA CRNDE is involved in resistance to EGFR tyrosine kinase inhibitor in EGFR-mutant lung cancer via eIF4A3/MUC1/EGFR signaling

Satoshi Takahashi, Rintaro Noro, Masahiro Seike*, Chao Zeng, Masaru Matsumoto, Akiko Yoshikawa, Shinji Nakamichi, Teppei Sugano, Mariko Hirao, Kuniko Matsuda, Michiaki Hamada, Akihiko Gemma

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib-and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.

Original languageEnglish
Article number4005
JournalInternational journal of molecular sciences
Volume22
Issue number8
DOIs
Publication statusPublished - 2021 Apr 2

Keywords

  • CRNDE
  • Drug resistance
  • EGFR-TKI
  • EIF4A3

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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