Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, univ...Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.展开更多
Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKI...Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.展开更多
基金supported by the Science and Technology Program of China (2012ZX09103101-053)the Natural Science Foundation of Guangdong Province (52013050014183 and 2013CXZDA006)+1 种基金the Program for New Century Excellent Talents in University (D.M.Zhang)the project was supported by Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (D. M. Zhang)
文摘Multidrug resistance(MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence.Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.
基金supported by National Key R&D Program of China(2017YFC1703800)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036)+3 种基金National Science Foundation of China(81630095,81973340,81903634 and 81803566)National Science and Technology Major Project(2018ZX09711001-008-008)National High-level Personnel of Special Support Program(Dongmei Zhang),Natural Science Foundation of Guangdong Province(2019A1515010144)China Postdoctoral Science Foundation-funded project(2019T120793).
文摘Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.
