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

doi:10.3390/ijms22084005

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.

Highlights

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown marked efficacy in non-small cell lung cancer (NSCLC) patients with EGFR mutations [1,2,3,4,5,6].Osimertinib showed significant efficacy in NSCLC patients with and without the T790M mutation in exon 20, which was previously considered a second-hit mutation [7,8]
We have previously reported that the miR-21, miR-134/487b/655, and miR-200 families can be used as therapeutic targets associated with EGFR-TKI treatment [10,11,12]
We evaluated the anti-tumor properties of afatinib and osimertinib in four EGFRmutant lung adenocarcinoma cell lines (i.e., PC-9, HCC827, H1975, and H1650) by the 3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay

Summary

Introduction

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown marked efficacy in non-small cell lung cancer (NSCLC) patients with EGFR mutations [1,2,3,4,5,6]. Osimertinib (a third-generation EGFR-TKI) showed significant efficacy in NSCLC patients with and without the T790M mutation in exon 20, which was previously considered a second-hit mutation [7,8]. Acquired mechanisms of resistance after treatment with osimertinib, including C797S mutation, activation of bypass pathway such as MET amplification, BRAF mutation, and transformation of small cell lung cancer have been previously reported [9]. We have previously reported that the miR-21, miR-134/487b/655, and miR-200 families can be used as therapeutic targets associated with EGFR-TKI treatment [10,11,12].

Methods

Results

Conclusion