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

Genomics, Proteomics & Bioinformatics

Available online 24 November 2022

Genomics, Proteomics & BioinformaticsAuthor links open overlay panelAbstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control ratio of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKI is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKI remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations, however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures method (PARIS) is used to establish the higher-order RNA structure maps of EGFR-TKI resistant and sensitive cells of NSCLC. Our results show RNA structural regions are enriched in untranslation regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N6-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKI. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential cancer therapy strategy is provided by using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.

Keywords

RNA structure

EGFR-TKI resistance

Non-small cell lung cancer

YRDC

ELAVL1

© 2022 The Authors. Published by Elsevier B.V. and Science Press on behalf of Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.

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