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Enhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug-Resistant Model and Genome-Wide siRNA Screening

文献类型： 外文期刊

作者： Shao, Fangyuan 1 ; Lyu, Xueying 1 ; Miao, Kai 1 ; Xie, Lisi 1 ; Wang, Haitao 1 ; Xiao, Hao 3 ; Li, Jie 1 ; Chen, Qiang 1 ; D 1 ;

作者机构： 1.Univ Macau, Fac Hlth Sci, Canc Ctr, Macau 999078, Peoples R China

2.Univ Macau, Fac Hlth Sci, Ctr Precis Med Res & Training, Macau 999078, Peoples R China

3.Guangdong Acad Agr Sci, Inst Anim Sci, Guangdong Key Lab Anim Breeding & Nutr, Guangzhou 510640, Peoples R China

4.Southern Univ Sci & Technol, Dept Biol, Shenzhen 518055, Peoples R China

5.Kiang Wu Hosp, Macau 820002, Peoples R China

6.Ctr Hosp Conde S Januario, Macau 820004, Peoples R China

7.Natl Ctr Adv Translat Sci, Div Preclin Innovat, NIH, Bethesda, MD 20892 USA

关键词： broad drug resistance; caspase 3 activation; patient-derived organoid; proteolysis; RNAi screening

期刊名称：ADVANCED SCIENCE （ 影响因子：16.806； 五年影响因子：17.835 ）

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收录情况： SCI

摘要： Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.

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