APE1 stimulates EGFR-TKI resistance by activating Akt signaling through a redox-dependent mechanism in lung adenocarcinoma.
APE1 stimulates EGFR-TKI resistance by activating Akt signaling through a redox-dependent mechanism in lung adenocarcinoma.
复制标题
APE1 通过肺腺癌中的氧化还原依赖性机制激活 Akt 信号传导来刺激 EGFR-TKI 耐药性
DOI：
10.1038/s41419-018-1162-0
复制
发表时间：
2018-10-31
影响因子：
9
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Lu GS;Li M;Xu CX;Wang D
表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)已成为激活EGFR突变的晚期肺腺癌(LUAD)患者的标准一线治疗药物。然而，大多数患者对EGFR-TKIs表现出获得性耐药，从而导致适度的总体生存益处。在此，我们发现APE1的表达水平与LUAD的TKI耐药密切相关。我们的临床数据显示，在EGFR突变的LUAD患者中，APE1水平与无进展生存率和中位进展时间呈负相关。此外，我们观察到与其亲本细胞株相比，TKI耐药的LUAD细胞系中APE1的表达增加。过表达APE1保护TKI敏感的LUAD细胞免受TKI诱导的细胞生长抑制和细胞死亡。相反，抑制APE1增强的TKI可诱导TKI耐药LUAD的细胞凋亡、细胞生长抑制和肿瘤生长抑制。此外，我们还发现APE1正向调节Akt的激活，并且APE1过表达诱导的TKI抵抗通过抑制Akt的活性而减弱。最后，我们证明了抑制APE1的氧化还原功能增强了耐TKI的LUAD细胞对TKI治疗的敏感性，并抑制了耐TKI的LUAD细胞中Akt的磷酸化，但不是通过抑制APE1DNA修复功能。综上所述，我们的数据显示，APE1的表达增加显著促进了LUAD对TKI的耐药性的发展，靶向APE1可能会逆转LUAD细胞对TKI治疗的获得性耐药性。此外，我们的数据显示，APE1通过氧化还原依赖的机制激活Akt信号来调节LUAD细胞对TKI的抵抗。
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line treatment for advanced lung adenocarcinoma (LUAD) cancer patients with activating EGFR mutations. However, most patients show acquired resistance to EGFR-TKIs, thereby resulting in a modest overall survival benefit. Here, we found that expression level of APE1 was closely associated with TKI resistance in LUAD. Our clinical data show that level of APE1 was inversely correlated with progression-free survival rate and median time to progression in EGFR-mutated LUAD patients. Additionally, we observed increased expression of APE1 in TKI-resistant LUAD cell lines compared to their parental cell lines. Overexpression of APE1-protected TKI-sensitive LUAD cells from TKI-induced cell growth inhibition and cell death. In contrast, inhibition of APE1-enhanced TKI-induced apoptosis, cell growth inhibition and tumor growth inhibition in TKI-resistant LUAD. In addition, we identified that APE1 positively regulates Akt activation and APE1 overexpression-induced TKI resistance was attenuated by inhibition of Akt activity. Finally, we demonstrated that inhibition of the redox function of APE1 enhances the sensitivity of TKI-resistant LUAD cells to TKI treatment and inhibits Akt phosphorylation in TKI-resistant LUAD cells, but not by inhibition of the APE1 DNA repair function. Taken together, our data show that increased expression of APE1 significantly contributes to TKI resistance development in LUAD, and targeting APE1 may reverse acquired resistance of LUAD cells to TKI treatment. Additionally, our data show that APE1 regulates TKI resistance in LUAD cells by activating Akt signaling through a redox-dependent mechanism.
登录
查看更多内容
DOI：
10.2147/dddt.s62963
发表时间：
2014
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Qian C;Li M;Sui J;Ren T;Li Z;Zhang L;Zhou L;Cheng Y;Wang D
通讯作者：
Wang D
影响因子：
5.6
作者：
Inamura K
通讯作者：
Inamura K
影响因子：
168.9
作者：
Goldstraw, Peter;Ball, David;Shepherd, Frances A.
通讯作者：
Shepherd, Frances A.
影响因子：
9.7
作者：
Xu, Cheng-Xiong;Jin, Hua;Cho, Myung-Haing
通讯作者：
Cho, Myung-Haing
影响因子：
37.3
作者：
Wu SG;Shih JY
通讯作者：
Shih JY