Background: Anlotinib resistance is a challenge for advanced non-small cell lung cancer (NSCLC). Understanding the underlying mechanisms against anlotinib resistance is of great importance to improve prognosis and treatment of patients with advanced NSCLC.
Methods: RT-qPCR assay was used to assess the level of miR-136-5p in anlotinib-resistant NSCLC cells and exosomes derived from anlotinib-resistant NSCLC cells. In addition, miR-136-5p level in tumor tissues from patients who exhibited a poor response to anlotinib therapy and patients who were therapy naïve or patients who exhibited a positive response to anlotinib therapy was detected by RT-qPCR assay.
Results: In this study, we found that high levels of plasma exosomal miR-136-5p is correlated with clinically poor anlotinib response. In addition, anlotinib-resistant NSCLC cells promoted parental NSCLC cell proliferation via transferring functional miR-136-5p from anlotinib-resistant NSCLC cells to parental NSCLC cells via exosomes. Moreover, exosomal miR-136-5p could endow NSCLC cells with anlotinib resistance by targeting PPP2R2A, leading to the activation of Akt pathway. Furthermore, miR-136-5p antagomir packaging into anlotinib-resistant NSCLC cell-derived exosomes functionally restored NSCLC cell anlotinib sensitivity in vitro. Animal studies showed that A549/anlotinib cell-derived exosomal miR-136-5p agomir promoted A549 cell anlotinib resistance in vivo.
Conclusion: Collectively, these findings indicated that anlotinib-resistant NSCLC cell-derived exosomal miR-136-5p confers anlotinib resistance in NSCLC cells by targeting PPP2R2A, indicating miR-136-5p may act as a potential biomarker for anlotinib response in NSCLC.



中文翻译：

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来自安罗替尼耐药的 NSCLC 细胞的外泌体 miR-136-5p 通过靶向 PPP2R2A 在非小细胞肺癌中赋予安罗替尼耐药性

背景：安罗替尼耐药是晚期非小细胞肺癌（NSCLC）面临的挑战。了解安罗替尼耐药的潜在机制对于改善晚期 NSCLC 患者的预后和治疗具有重要意义。
方法： RT-qPCR 检测用于评估安罗替尼耐药 NSCLC 细胞和安罗替尼耐药 NSCLC 细胞衍生的外泌体中 miR-136-5p 的水平。此外，通过 RT-qPCR 测定法检测了对安罗替尼治疗反应不佳的患者和未接受过治疗的患者或对安罗替尼治疗表现出阳性反应的患者的肿瘤组织中 miR-136-5p 水平。
结果：在这项研究中，我们发现高水平的血浆外泌体 miR-136-5p 与临床上较差的安罗替尼反应相关。此外，耐安罗替尼的 NSCLC 细胞通过外泌体将功能性 miR-136-5p 从耐安罗替尼的 NSCLC 细胞转移至亲代 NSCLC 细胞，从而促进亲代 NSCLC 细胞的增殖。此外，外泌体 miR-136-5p 可通过靶向 PPP2R2A 使 NSCLC 细胞对安罗替尼产生耐药性，从而激活 Akt 通路。此外，将 miR-136-5p antagomir 包装到耐安罗替尼的 NSCLC 细胞衍生的外泌体中，在体外功能上恢复了 NSCLC 细胞对安罗替尼的敏感性。动物研究表明，A549/安罗替尼细胞衍生的外泌体 miR-136-5p agomir 在体内促进了 A549 细胞对安罗替尼的耐药性。
结论：总的来说，这些发现表明，安罗替尼耐药的 NSCLC 细胞来源的外泌体 miR-136-5p 通过靶向 PPP2R2A 在 NSCLC 细胞中赋予安罗替尼耐药性，表明 miR-136-5p 可能作为安罗替尼在 NSCLC 中反应的潜在生物标志物。