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RNA Structural Dynamics Modulate EGFR-TKI Resistance Through Controlling YRDC Translation in NSCLC Cells

Boyang Shi1, Ke An1, Yueqin Wang2

  • 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.

Genomics, Proteomics & Bioinformatics
|November 26, 2022
PubMed

Insights

RNA structure changes in non-small cell lung cancer (NSCLC) cells can lead to resistance against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Targeting RNA structure offers a new therapeutic strategy for overcoming EGFR-TKI resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • RNA Biology

Background:

  • Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are crucial for non-small cell lung cancer (NSCLC) treatment.
  • Acquired resistance to EGFR-TKIs presents a significant clinical challenge, with underlying mechanisms often poorly understood.
  • The role of RNA structures in cancer drug resistance is an emerging area of investigation.

Purpose of the Study:

  • To investigate the role of higher-order RNA structures in EGFR-TKI resistance in NSCLC.
  • To identify specific RNA structures and regulatory mechanisms involved in modulating sensitivity or resistance to EGFR-TKIs.
  • To explore potential therapeutic strategies targeting RNA structure for overcoming EGFR-TKI resistance.

Main Methods:

  • Utilized the psoralen analysis of RNA interactions and structures (PARIS) method to map higher-order RNA structures in EGFR-TKI-resistant and -sensitive NSCLC cells.
  • Analyzed the correlation between RNA structural regions, untranslated regions (UTRs), and translation efficiency (TE).
  • Investigated the function of yrdC N⁶-threonylcarbamoyltransferase domain containing (YRDC) and its interaction with embryonic lethal abnormal vision-like 1 (ELAVL1) in regulating EGFR-TKI sensitivity.

Main Results:

  • Identified enriched RNA structural regions within untranslated regions (UTRs), correlating with translation efficiency.
  • Demonstrated that yrdC N⁶-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs.
  • Showed that RNA structure formation in the YRDC 3' UTR inhibits ELAVL1 binding, thereby impairing YRDC translation and conferring EGFR-TKI sensitivity.

Conclusions:

  • RNA structure plays a critical role in modulating EGFR-TKI resistance in NSCLC.
  • The YRDC mRNA's RNA structure influences its translation via ELAVL1 binding, presenting a novel mechanism for resistance.
  • Targeting RNA structure, for example, using antisense oligonucleotides (ASOs), represents a potential therapeutic avenue for overcoming EGFR-TKI resistance in NSCLC.
Keywords:
EGFR-TKI resistanceELAVL1Non-small cell lung cancerRNA structureYRDC

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