Unlocking KRAS: Navigating Its Molecular Biology and Treatment Landscape Among Gastrointestinal Malignancies

<i>KRAS</i>-targeted therapy has opened new doors in the world of oncology, and many trials are underway for <i>KRAS</i> specific treatments for gastrointestinal (GI) malignancies. Outlining the current state of <i>KRAS</i> therapy and the remaining research gaps pertaining to these deadly cancers is crucial for the development of future therapeutics. In this review, we focus on the relationship between <i>KRAS</i> and GI malignancies. Current therapies are discussed with an in-depth exploration of the <i>KRAS</i> gene and how it connects to pancreatic, colorectal and other GI malignancies. Promising clinical trials and future therapies are highlighted while discussing the molecular biology behind them. Specifically, trials focusing on upcoming <i>KRAS</i> on and off inhibitors in development as well as variant focused inhibitors targeting the more common mutations G12D and G12V. We discuss exciting new pan/multi <i>KRAS</i> inhibitors that have been successful in pre-clinical trials. More unique therapeutic options include <i>KRAS</i> T cell therapies, vaccines, and combination strategies with immunotherapy. Furthermore, we address the difficulties with <i>KRAS</i> therapy, and the potential future directions needed to overcome them. An in-depth current literature review was done along with a review of the active clinical trials for <i>KRAS</i>-targeted therapeutics involving GI malignancies.