Poster Presentation 40th Annual Lorne Genome Conference 2019

Systematic Functional Identification of Cancer Multi-Drug Resistance Genes (#181)

Man Tat Lau 1 , Shila Ghazanfar 2 3 , Ashleigh Parkin 4 , Angela Chou 4 5 , Jean Yang 2 , Marina Pajic 4 5 , Gregory Neely 1
  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, Australia
  2. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia
  3. The Judith and David Coffey Life Lab, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
  4. The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, Sydney, NSW, Australia
  5. The University of Sydney, Sydney, NSW, Australia

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. 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 41 multi-drug resistance genes, including an uncharacterised gene (named here Required for Drug-induced Death 1; RDD1). Loss of RDD1 resulted in resistance to five anti-cancer drugs, and RDD1 was required for an anti-tubulin drug to trigger MCL-1 degradation and cell death. Low RDD1 expression was associated with poor prognosis in multiple cancers. Together, we provide the first functional landscape of resistance mechanisms to a broad range of chemotherapeutic drugs and reveal new multi-drug resistance nodes. This information can guide personalised therapies or instruct rational drug combinations to minimise acquisition of resistance.