Abstract 2133: Systematic mapping of genetic interactions in human cancer cells reveals context dependent cancer signaling pathways

Genetic interaction screens have long been used to map gene functions and cellular pathways in model organisms and more recently in human cells. However, due to the technical challenges of these maps, most studies in human cells have focused on a single cell line, limiting the ability to determine how different genetic and cellular contexts influence genetic interactions. Here, we engineered a 110,728-element combinatorial CRISPR-Cas9 library to systematically map 12,282 genetic interactions among tumor suppressor genes and druggable targets. We mapped the landscape of genetic interactions in cell lines from breast cancer, head and neck squamous carcinoma, and non-small cell lung cancer as well as in non-cancerous, epithelial cells. The resulting genetic interaction maps emphasize the context dependency of these interactions. Of the interactions that are conserved across multiple cell lines, many include frequently essential genes, suggesting that these interactions may be critical for fundamental cellular functions. We found that genetic interaction maps from cancer cell lines are more similar to one another than non-cancer interaction maps, even between cancer and normal cells from the same tissue. Subsequent targeted chemogenetic screens confirmed interaction hubs across multiple cell lines while highlighting the robustness of some of the strongest interactions. Many of the identified genetic interactions suggest therapeutic interventions, such as the combination of CDK4 and MAPK inhibitors. Using the tissue-specific genetic interaction networks, we also built a deep learning model that accurately predicts patient outcomes, outperforming models that use accepted biomarkers such as MammaPrint. In summary, these genetic interaction maps provide a broad resource to investigate context dependency in cancer signaling pathways and in cancer drug response. Citation Format: Samson H. Fong, Brent M. Kuenzi, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Jeff Hager, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Trey Ideker. Systematic mapping of genetic interactions in human cancer cells reveals context dependent cancer signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2133.