Systematic functional identification of cancer drug resistance genes

Lau MT and Neely GG

The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney NSW 2006, Australia.

Cancer drug resistance is a major obstacle in cancer therapy. To elucidate the genetic factors that regulate sensitivity to anti-cancer drugs, we performed whole genome CRISPR/Cas9 knockout screens for resistance to a spectrum of anti-cancer drugs of varying compositions and general or targeted mechanisms of action. In addition to known 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. Anti-cancer drugs could be classified based on resistance mechanisms, and we provide the first functional “phylogenecity” for these compounds. Importantly, we identified 49 multi-drug resistance genes, including a previously uncharacterised gene named here Required for Drug-induced Death 1; RDD1greg. Loss of RDD1 resulted in resistance to five anti-cancer drugs, primarily anti-tubulin agents, and RDD1 is required for an anti-tubulin drug to trigger MCL-1 degradation and cell death. Loss of RDD1 also conferred resistance to anti-tubulin therapy in a mouse xenograft model, and clinically, low RDD1 expression was associated with poor prognosis in multiple cancer cohorts, with the strongest association for ovarian cancer patient outcome. 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 anti-cancer therapies or instruct rational drug combinations designed to minimise acquisition of resistance.