Systematic functional identification of cancer multi-drug resistance genes

Background Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs. Results In addition to known drug targets and resistance mechanisms, thi...

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Veröffentlicht in:Genome Biology Jg. 21; H. 1; S. 27
Hauptverfasser: Lau, Man-Tat, Ghazanfar, Shila, Parkin, Ashleigh, Chou, Angela, Rouaen, Jourdin R., Littleboy, Jamie B., Nessem, Danielle, Khuong, Thang M., Nevoltris, Damien, Schofield, Peter, Langley, David, Christ, Daniel, Yang, Jean, Pajic, Marina, Neely, G. Gregory
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 07.02.2020
Springer Nature B.V
BMC
Schlagworte:
Animal Genetics and Genomics
Apoptosis
Bioinformatics
Biomedical and Life Sciences
Biosynthesis
Cancer
cancer therapy
Cell cycle
Chemoresistance
Chemotherapy
CRISPR
CRISPR-Cas systems
Cytotoxicity
death
Deoxyribonucleic acid
Dihydrofolate reductase
DNA
DNA repair
Drug delivery
Drug resistance
Drug Resistance, Neoplasm - genetics
drug therapy
drugs
Evolutionary Biology
Gene expression
genes
Genetic factors
Genomes
Genomics
HEK293 Cells
HeLa Cells
Human Genetics
Humans
Kinases
Life Sciences
Microbial Genetics and Genomics
Multidrug resistance
multiple drug resistance
Plant Genetics and Genomics
prognosis
RNA polymerase
Therapeutic targets
ISSN:1474-760X, 1474-7596, 1474-760X
Online-Zugang:Volltext
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Zusammenfassung:Background Drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed CRISPR-Cas9 knockout screens for resistance to a spectrum of drugs. Results In addition to known drug targets and resistance mechanisms, this study revealed novel insights into drug mechanisms of action, including cellular transporters, drug target effectors, and genes involved in target-relevant pathways. Importantly, we identified ten multi-drug resistance genes, including an uncharacterized gene C1orf115 , which we named Required for Drug-induced Death 1 ( RDD1 ). Loss of RDD1 resulted in resistance to five anti-cancer drugs. Finally, targeting RDD1 leads to chemotherapy resistance in mice and low RDD1 expression is associated with poor prognosis in multiple cancers. Conclusions Together, we provide a functional landscape of resistance mechanisms to a broad range of chemotherapeutic drugs and highlight RDD1 as a new factor controlling multi-drug resistance. This information can guide personalized therapies or instruct rational drug combinations to minimize acquisition of resistance.
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ISSN:1474-760X
1474-7596
1474-760X
DOI:10.1186/s13059-020-1940-8