LAUSR

Simple Summary Despite recent dramatic progress, developing drugs that target oncogenic KRAS or its key effectors remains a major challenge for cancer research. Improving our understanding of the underlying biology of KRAS in cancer will identify potential codependent vulnerabilities or synthetic lethal partners that are essential specifically in the context of KRAS mutations. Aberrant alterations in the KRAS oncogene not only favor cancer cell survival and proliferation, but also trigger oncogenic stress and compensatory mechanisms in cancer cells. These effectors are, thus, rational targets for defining synthetic lethal approaches to form the basis for effective therapies directed at KRAS-mutant tumors. Abstract Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.