Systematic functional identification of cancer multi-drug resistance genes
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.
|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|
|Publisher Name||GENOME BIOLOGY|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/32028983|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/15308|