Division of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan.
Department of Electrical Engineering and Bioscience, Faculty of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan.
Int J Mol Sci. 2021 Apr 13;22(8):4005. doi: 10.3390/ijms22084005.
(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.
(1) 背景：表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）获得性耐药是许多临床肿瘤学家面临的一个棘手问题。EGFR-TKIs 耐药的机制较为复杂，长链非编码 RNA（lncRNA）可能在肿瘤发生和转移中发挥重要作用。然而，lncRNA 与 EGFR 突变型肺癌耐药之间的生物学过程在很大程度上仍不清楚。(2) 方法：采用逐步法建立奥希替尼和阿法替尼耐药的 EGFR 突变型肺癌细胞。对亲本和耐药的 EGFR 突变型非小细胞肺癌（NSCLC）细胞进行非编码和编码 RNA 的微阵列分析，并通过医学工业合作进行生物信息学分析进行评估。(3) 结果：通过微阵列分析，结直肠癌差异表达（CRNDE）和 DiGeorge 综合征关键区域基因 5（DGCR5）lncRNA 在 EGFR-TKI 耐药细胞中高表达。RNA-蛋白质结合分析显示真核翻译起始因子 4A3（eIF4A3）以重叠的方式与 CRNDE 和 DGCR5 结合。CRNDE 下调 eIF4A3、黏蛋白 1（MUC1）和磷酸化 EGFR 的表达。抑制 CRNDE 激活了 eIF4A3/MUC1/EGFR 信号通路和细胞凋亡活性，并恢复了对 EGFR-TKIs 的敏感性。(4) 结论：结果表明，CRNDE 与 EGFR-TKIs 耐药的发展有关。CRNDE 可能是克服 EGFR 突变型 NSCLC 的新的治疗靶点。
