Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer
Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer
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DOI：
10.21873/anticanres.13667
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发表时间：
2019-09-01
影响因子：
2
通讯作者：
Yamamoto, Masahiro
中科院分区：
文献类型：
--
作者：
Sanomachi, Tomomi;Suzuki, Shuhei;Yamamoto, Masahiro
背景/目的：尽管表皮生长因子受体(EGFR)在肺癌和胰腺癌中经常被激活，但EGFR酪氨酸激酶抑制剂(EGFR-TKIs)的疗效有限。最近，抗精神病药物布雷西哌唑被报道通过抑制抗凋亡蛋白Survivin来增加胶质瘤细胞对第三代EGFR-TKI奥西美替尼的化疗敏感性，但它们对肺癌和胰腺癌的联合作用尚不清楚。本研究的目的是检测布雷克哌唑和奥西美替尼在体外和体内对肺癌和胰腺癌细胞的联合作用。材料和方法：应用Survivin、siRNA和免疫印迹抑制物YM155检测Survivin在奥西莫替尼耐药中的作用。台盼蓝染色检测药物对体外培养细胞活力的影响。通过异种移植小鼠模型检测药物对肿瘤生长的体内影响。结果：灯盏花素与奥西美替尼在体外具有联合作用。Survivin的药理和遗传抑制使细胞对奥西美替尼增敏。此外，布雷西哌唑和奥西美替尼的联合使用有效地抑制了小鼠异种移植模型中的肿瘤生长。结论：灯盏花素与奥西美替尼联合应用治疗肺癌、胰腺癌具有较好的应用前景。
Background/Aim: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic cancer cells in vitro and in vivo. Materials and Methods: YM155, a suppressor of survivin, siRNA, and immunoblot were used to examine the role of survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model. Results: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model. Conclusion: Brexpiprazole is a promising drug for lung and pancreatic cancer in combination with osimertinib.