Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment.
Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment.
复制标题
DOI：
10.1016/j.omto.2020.10.009
复制
发表时间：
2020-12-16
期刊：
影响因子：
--
通讯作者：
Inazawa J
中科院分区：
文献类型：
--
作者：
Inoue J;Fujiwara K;Hamamoto H;Kobayashi K;Inazawa J
对于皮肤鳞状细胞癌（cSCC），对于不适合或拒绝手术的患者，局部治疗是必不可少的选择。表皮生长因子受体（EGFR）在cSCC的发展中起着关键作用，但EGFR酪氨酸激酶抑制剂（TKIs），如吉非替尼，在该疾病中仅显示出部分临床益处。因此，需要开发新的策略来提高TKIs在cSCC中的疗效。我们之前证明了肿瘤抑制microRNA (miRNA) miR-634作为细胞保护性癌细胞存活过程的负调节因子，是一种有用的抗癌治疗剂。在本研究中，我们发现局部应用含有miR-634的软膏可以抑制cSCC异种移植小鼠模型和7,12-二甲基苯[a]蒽(DMBA)/12- o -十四烷酰基酚-13-乙酸（TPA）诱导的乳头瘤小鼠模型的体内肿瘤生长而没有毒性。功能验证显示，miR-634过表达通过直接靶向谷氨酰胺转运蛋白ASCT2来减少谷氨酰胺水解。此外，miR-634的过表达通过在体外和体内引发严重的能量应激，协同增强了tki诱导的细胞毒性。因此，我们建议用miR-634软膏局部治疗是改善基于EGFR tki的cSCC治疗的有用策略。在这项研究中，Inoue等人证明，miR-634软膏局部治疗可提高EGFR酪氨酸激酶抑制剂（TKI）对皮肤鳞状细胞癌（cSCC）的疗效，通过同时靶向多种细胞保护过程，包括自噬、抗氧化清除剂、抗凋亡和谷氨酰胺水解，引发严重的能量应激。
For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) miR-634 functions as a negative modulator of the cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. In the present study, we found that topical application of an ointment containing miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2, a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo. Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC. In this study, Inoue et al. demonstrate that topical treatment with miR-634 ointment improves the efficacy of EGFR tyrosine kinase inhibitor (TKI) for cutaneous squamous cell carcinoma (cSCC) by triggering severe energetic stress via concurrent targeting of multiple cytoprotective processes, including autophagy, antioxidative scavenger, anti-apoptosis, and glutaminolysis.
登录
查看更多内容
影响因子：
1.5
作者：
Fayne, Rachel;Nanda, Sonali;Shen, John
通讯作者：
Shen, John
影响因子：
2.4
作者：
Collins, Alexandra;Savas, Jessica;Doerfler, Laura
通讯作者：
Doerfler, Laura
影响因子：
8.8
作者：
Hong, David S.;Kang, Yoon-Koo;Beg, Muhammad S.
通讯作者：
Beg, Muhammad S.
影响因子：
1.5
作者：
Frazier, Kendall S.
通讯作者：
Frazier, Kendall S.
影响因子：
11.2
作者：
Chou, Ting-Chao
通讯作者：
Chou, Ting-Chao