NF-κB和AICDA的共抑制克服非小细胞肺癌中获得性表皮生长因子受体酪氨酸激酶抑制剂耐药性
Cosuppression of NF-κB and AICDA Overcomes Acquired EGFR-TKI Resistance in Non-Small Cell Lung Cancer.
作者信息
Yeo Min-Kyung, Kim Yoonjoo, Lee Da Hye, Chung Chaeuk, Bae Go Eun
机构信息
Department of Pathology, School of Medicine, Chungnam National University, Daejeon 35015, Korea.
Division of Pulmonology, Department of Internal Medicine School of Medicine, Chungnam National University, Daejeon 35015, Korea.
出版信息
Cancers (Basel). 2022 Jun 14;14(12):2940. doi: 10.3390/cancers14122940.
BACKGROUND
Acquired resistance after EGFR-tyrosine kinase inhibitor (TKI) treatment is the rule rather than the exception. Overcoming resistance to EGFR-TKIs is essential if we are to develop better therapeutic strategies for lung cancer patients. Here, we examine the effector signaling pathways underlying TKI resistance and propose targets to overcome the resistance of lung adenocarcinoma (LAC) to TKI.
METHODS
We compared the expression of NF-κB, AICDA, Akt, IL-6, Jak2, and Stat3 by EGFR-TKI-resistant and EGFR-TKI-sensitive LAC cell lines, and by LAC patients treated with EGFR-TKIs; we then evaluated links between expression and treatment responses. We also examined the therapeutic effects of NF-κB and AICDA inhibition in EGFR-TKI-resistant LACs.
RESULTS
NF-κB and AICDA were more expressed by EGFR-TKI-resistant LACs than by EGFR-TKI-sensitive LACs. EGFR-TKIs induced a dose-dependent increase in the expression of NF-κB, AICDA, and IL-6. Inhibition of NF-κB suppressed the expression of AICDA, Akt, and IL-6 in EGFR-TKI-resistant and EGFR-TKI-sensitive LACs, whereas knockdown of AICDA suppressed the expression of NF-κB and Akt in both cell types. Treating EGFR-TKI-resistant LACs with an EGFR-TKI, alongside cosuppression of NF-κB and AICDA, had a significant therapeutic effect.
CONCLUSION
Treatment with an EGFR-TKI plus cosuppression of NF-κB and AICDA may be a promising strategy to overcome EGFR-TKI resistance in LACs.
背景
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗后获得性耐药是普遍现象而非个别情况。若要为肺癌患者制定更好的治疗策略，克服对EGFR-TKIs的耐药性至关重要。在此，我们研究了TKI耐药背后的效应信号通路，并提出克服肺腺癌（LAC）对TKI耐药的靶点。
方法
我们比较了EGFR-TKI耐药和EGFR-TKI敏感的LAC细胞系以及接受EGFR-TKIs治疗的LAC患者中NF-κB、AICDA、Akt、IL-6、Jak2和Stat3的表达；然后评估了表达与治疗反应之间的联系。我们还研究了NF-κB和AICDA抑制对EGFR-TKI耐药LACs的治疗效果。
结果
EGFR-TKI耐药的LACs中NF-κB和AICDA的表达高于EGFR-TKI敏感的LACs。EGFR-TKIs诱导NF-κB、AICDA和IL-6的表达呈剂量依赖性增加。抑制NF-κB可抑制EGFR-TKI耐药和EGFR-TKI敏感LACs中AICDA、Akt和IL-6的表达，而敲低AICDA可抑制两种细胞类型中NF-κB和Akt的表达。用EGFR-TKI治疗EGFR-TKI耐药的LACs，同时共抑制NF-κB和AICDA，具有显著的治疗效果。
结论
EGFR-TKI联合共抑制NF-κB和AICDA可能是克服LACs中EGFR-TKI耐药的一种有前景的策略。
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