EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer
| العنوان: | EGFR TKIs impair lysosome-dependent degradation of SQSTM1 to compromise the effectiveness in lung cancer |
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| المؤلفون: | Muchun Li, Neelum Aziz Yousafzai, Hongchuan Jin, Shilong Ying, Yiran Zhu, Huimin An, Ping Song, Wenxia Xu, Xiangtong Zhao, Zhiguo Zhang, Miaoqin Chen, Lifeng Feng, Liyuan Zhu, Shiman Hu, Xian Wang, Tingting Jiang, Lixian Yang |
| المصدر: | Signal Transduction and Targeted Therapy Signal Transduction and Targeted Therapy, Vol 4, Iss 1, Pp 1-11 (2019) |
| بيانات النشر: | Nature Publishing Group UK, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Cancer therapy, medicine.medical_treatment, lcsh:Medicine, Article, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Gefitinib, In vivo, Lysosome, Genetics, medicine, Epidermal growth factor receptor, Lung cancer, lcsh:QH301-705.5, biology, business.industry, lcsh:R, medicine.disease, In vitro, respiratory tract diseases, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), 030220 oncology & carcinogenesis, Cancer research, biology.protein, business, Tyrosine kinase, medicine.drug |
| الوصف: | Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy. |
| اللغة: | English |
| تدمد: | 2059-3635 2095-9907 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd65ec5964b509b808a89bbbabd065feTest http://europepmc.org/articles/PMC6799834Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bd65ec5964b509b808a89bbbabd065fe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20593635 20959907 |
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