Abstract：
The mechanism of tumor drug resistance is complex and may involve stem cell maintenance, epithelial-mesenchymal transition, the activation of survival signaling pathways, transporter protein expression, and tumor microenvironment remodeling, all of which are linked to γ-secretase/Notch signaling. Increasing evidence has shown that the activation of the γ-secretase/Notch pathway is a key driver of cancer progression and drug resistance development and that γ-secretase inhibitors (GSIs) may be the most promising agents for reversing chemotherapy resistance of tumors by targeting the γ-secretase/Notch pathway. Here, we systematically summarize the roles in supporting γ-secretase/Notch activation-associated transformation of cancer cells into cancer stem cells, promotion of the EMT process, PI3K/Akt, MEK/ERK and NF-κB activation, enhancement of ABC transporter protein expression, and TME alteration in mediating tumor drug resistance. Subsequently, we analyze the mechanism of GSIs targeting the γ-secretase/Notch pathway to reverse tumor drug resistance and propose the outstanding advantages of GSIs in treating breast cancer drug resistance over other tumors. Finally, we emphasize that the development of GSIs for reversing tumor drug resistance is promising.
摘要：
肿瘤耐药机制复杂,可能涉及干细胞维持,上皮-间质转化，存活信号通路的激活，转运蛋白表达，和肿瘤微环境重塑，所有这些都与γ-分泌酶/Notch信号连接。越来越多的证据表明，γ-分泌酶/Notch途径的激活是癌症进展和耐药性发展的关键驱动因素，γ-分泌酶抑制剂（GSI）可能是通过靶向逆转肿瘤化疗耐药性的最有希望的药物。γ-分泌酶/Notch途径。这里,我们系统地总结了支持γ-分泌酶/Notch激活相关的癌细胞转化为癌症干细胞的作用，EMT流程的推广，PI3K/Akt,MEK/ERK和NF-κB激活，ABC转运蛋白表达的增强，和TME改变介导肿瘤耐药。随后，我们分析了GSIs靶向γ-分泌酶/Notch通路逆转肿瘤耐药的机制，并提出了GSIs在治疗乳腺癌耐药方面优于其他肿瘤的突出优势。最后,我们强调，用于逆转肿瘤耐药性的GSI的开发是有希望的。
