An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic RIT1 in lung cancer

Advances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor9s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred to lung cancer cells by differing cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines together with small molecule drug sensitivity profiling identified a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators, such as Aurora kinase A and USP9X. We find that oncogenic RIT1M90I alters mitotic timing, suggesting that RIT1-mutant cells have a weakened spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant cancer.