Open AccessEnhanced Protein Damage Clearance Induces Broad Drug Resistance in Multitype of Cancers Revealed by an Evolution Drug‐Resistant Model and Genome‐Wide siRNA Screening
Author(s) -
Shao Fangyuan,
Lyu Xueying,
Miao Kai,
Xie Lisi,
Wang Haitao,
Xiao Hao,
Li Jie,
Chen Qiang,
Ding Renbo,
Chen Ping,
Xing Fuqiang,
Zhang Xu,
Luo GuangHui,
Zhu Wenli,
Cheng Gregory,
Lon Ng Wai,
Martin Scott E.,
Wang Guanyu,
Chen Guokai,
Dai Yunlu,
Deng ChuXia
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202001914
Subject(s) - drug resistance , proteasome , bortezomib , drug , cisplatin , proteasome inhibitor , pharmacology , mechanism (biology) , cancer research , medicine , abcg2 , chemistry , biology , atp binding cassette transporter , gene , immunology , chemotherapy , biochemistry , genetics , multiple myeloma , transporter , philosophy , epistemology
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.