Selumetinib通过调节MIG6/STAT3在NSCLC中克服吉非替尼的原发性和获得性耐药。

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL Archives of Pharmacal Research Pub Date : 2023-11-30 DOI:10.1007/s12272-023-01471-0
Xiaoping Song, Lina Wang, Wei Tang, Luyao Yuan, Qingchao Liu, Jing Li, Daidi Fan
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引用次数: 0

摘要

吉非替尼作为第一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),在治疗非小细胞肺癌(NSCLC)方面取得了很大进展,但不可避免地会出现耐药性。因此,探索吉非替尼耐药机制,开发新的联合治疗策略具有重要意义。在我们的研究中,结果显示selumetinib (AZD6244)与吉非替尼协同抑制NSCLC的增殖。Selumetinib还增强了吉非替尼耐药肺癌细胞系中吉非替尼诱导的细胞凋亡和迁移抑制能力。随后,通过STRING数据库和western blotting实验观察并验证了MIG6和STAT3之间的负调控。在吉非替尼耐药细胞中,与selumetinib共处理时,STAT3的持续激活显著下调。然而,塞鲁美替尼和吉非替尼联合导致的p-STAT3的下调被MIG6的缺失所抵消,这表明塞鲁美替尼通过调节非小细胞肺癌中MIG6/STAT3来增强吉非替尼的敏感性。相比之下,当MIG6过表达时,吉非替尼和塞鲁美替尼治疗后p-STAT3进一步受到抑制。此外,塞鲁美替尼与吉非替尼联用有效促进了肺癌异种移植物体内对吉非替尼的敏感性,肿瘤抑制率达到81.49%,而吉非替尼单药组的肿瘤抑制率仅为31.95%。综上所述,MIG6/STAT3负调控在STAT3的持续激活和对EGFR-TKIs的抗性中起着重要作用。我们的研究还提示,EGFR-TKIs联合MEK1/2抑制剂(如selumetinib)可能有利于那些对EGFR-TKIs产生原发性或获得性耐药的NSCLC患者,为TKIs联合selumetinib在临床癌症治疗中的应用提供理论支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Selumetinib overcomes gefitinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC

Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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