(41a) The Landscape of Metabolic Pathway Dependencies in Cancer Cell Lines

The metabolic reprogramming of cancer cells creates metabolic vulnerabilities that can be therapeutically targeted. However, our understanding of metabolic dependencies and the pathway crosstalk that creates these vulnerabilities in cancer cells remains incomplete. Previous analyses of metabolic vulnerabilities in cancer cells have been limited to the analysis of individual genes or metabolites. Here, by integrating gene expression data with genetic loss-of-function and pharmacological screening data from hundreds of cancer cell lines, we developed a computational method to answer the question: when a metabolic pathway’s activity is high, which other metabolic pathways become more essential or less essential? Using this approach, we identified metabolic vulnerabilities at the level of pathways rather than individual genes. This approach revealed that metabolic pathway dependencies are highly context-specific such that cancer cells are vulnerable to inhibition of one metabolic pathway only when activity of another metabolic pathway is altered. For example, we found that identifying key regulators of metabolic pathways, such as the Pentose Phosphate Pathway, may serve as a biomarker to identify which patients may benefit from antifolate chemotherapies (e.g. methotrexate, 5-fluorouracil). Notably, we also found that the no single metabolic pathway was universally essential, suggesting that cancer cells are not invariably dependent on any metabolic pathway. In addition, we confirmed that cell culture medium is a major confounding factor for the analysis of metabolic pathway vulnerabilities. Nevertheless, we found robust associations between metabolic pathway activity and sensitivity to clinically approved drugs that were independent of cell culture medium. Lastly, we used parallel integration of pharmacological and genetic dependency data to confidently identify metabolic pathway vulnerabilities. Taken together, this study serves as a comprehensive characterization of the landscape of metabolic pathway vulnerabilities in cancer cell lines.