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Systematic functional identification of cancer multi-drug resistance genes

Abstract

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.

Type Journal
Authors Lau MT., Ghazanfar S., Parkin A., Chou A., Rouaen JR., Littleboy JB., Nessem D., Khuong TM., Nevoltris D., Schofield P., Langley D., Christ D., Yang J., Pajic M., Neely GG.
Responsible Garvan Author Prof Daniel Christ
Publisher Name GENOME BIOLOGY
Published Date 2020-02-07
Published Volume 21
Published Issue 1
Status Always Electronic
DOI https://doi.org/10.1186/s13059-020-1940-8
URL link to publisher's version https://genomebiology.biomedcentral.com/articles/10.1186/s13059-020-1940-8#author-information