Systematic functional identification of cancer multi-drug resistance genes

Man-Tat Lau(The University of Sydney), Shila Ghazanfar(The University of Sydney), Ashleigh Parkin(Garvan Institute of Medical Research), Angela Chou(The University of Sydney), Jourdin R.C. Rouaen(The University of Sydney), Jamie B. Littleboy(The University of Sydney), Danielle Nessem(Garvan Institute of Medical Research), Thang M. Khuong(The University of Sydney), Damien Névoltris(Garvan Institute of Medical Research), Peter R. Schofield(Garvan Institute of Medical Research), D.B. Langley(Garvan Institute of Medical Research), Daniel Christ(Garvan Institute of Medical Research), Jean Yang(The University of Sydney), Marina Pajic(Garvan Institute of Medical Research), G. Gregory Neely(The University of Sydney)
Genome biology
February 7, 2020
10.1186/s13059-020-1940-8
Cited by 43Open Access
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Abstract

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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