2. Academic Validation
  3. Systematic functional identification of cancer multi-drug resistance genes

Systematic functional identification of cancer multi-drug resistance genes

  • Genome Biol. 2020 Feb 7;21(1):27. doi: 10.1186/s13059-020-1940-8.
Man-Tat Lau 1 2,  Shila Ghazanfar 3 4,  Ashleigh Parkin 5,  Angela Chou 5 6,  Jourdin R Rouaen 1,  Jamie B Littleboy 1,  Danielle Nessem 5,  Thang M Khuong 1,  Damien Nevoltris 7,  Peter Schofield 7 8,  David Langley 7,  Daniel Christ 7 8,  Jean Yang 3,  Marina Pajic 9 10,  G Gregory Neely 11 12
Affiliations

Affiliations

  • 1 The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 2 Genome Editing Initiative, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 3 School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 4 The Judith and David Coffey Life Lab, Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
  • 5 The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
  • 6 The University of Sydney, Sydney, NSW, 2006, Australia.
  • 7 Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, 2010, Australia.
  • 8 St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, Sydney, NSW, 2010, Australia.
  • 9 The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia. [email protected].
  • 10 St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, Sydney, NSW, 2010, Australia. [email protected].
  • 11 The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW, 2006, Australia. [email protected].
  • 12 Genome Editing Initiative, The University of Sydney, Sydney, NSW, 2006, Australia. [email protected].
PMID: 32028983 DOI: 10.1186/s13059-020-1940-8
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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