Grant: Travel Awards - Institute Community Support

Cancer cells reshape their metabolism to meet the increased demand for the building blocks required to fuel rapid growth and proliferation, which provides a unique target for cancer therapeutic intervention. Indeed, several drugs that inhibit metabolic reactions are currently tested in clinical trials but resistance to these drugs is common. This highlights the need for a better understanding of the vulnerabilities of metabolically perturbed cells to provide rational for combination therapies to avoid drug resistance. To gain further insight into the interplay between cellular pathways, we aim to identify genes which when disrupted cause an unexpected effect on proliferation in cells with a metabolic perturbation compared to wild type cells. Such co-dependencies between gene pairs, termed "genetic interactions" (GIs), hold great potential for identifying novel genetic vulnerabilities and drug adaptation mechanisms. Using CRISPR-Cas technology, which provides an efficient tool to perturb genes on a genome scale, we screened for genes required for proliferation in a collection of cancer query cell lines, each of which carries a single gene knockout of a metabolic gene. Comparison of the effect of each disrupted gene between wild type and query lines enabled the identification of GIs with metabolic genes. These systematic genetic screens captured known dependencies between metabolic genes but also revealed a large set of novel GIs with genes of known and unknown function. Importantly, many of the discovered interaction pairs are potentially druggable and therefore will be further studied for their therapeutic potential. In summary, the research performed revealed a genetic interaction network centered on cellular metabolism. These insights could serve as a discovery tool to provide rational for novel combination therapies with the goal to improve cancer therapy for Canadians.