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

## TL;DR

This review explores the role of KRAS in gastrointestinal cancers and the progress in developing targeted therapies, emphasizing the need for combination treatments and personalized approaches.

## Contribution

The paper provides a comprehensive overview of current and emerging KRAS-targeted therapies for gastrointestinal malignancies, highlighting new drug developments and challenges.

## Key findings

- KRAS-targeted therapies show promise but often face resistance due to tumor adaptation.
- Combination therapies and personalized treatment approaches are critical for improving outcomes.
- New KRAS inhibitors and immunotherapy strategies are being tested in clinical trials.

## Abstract

Kirsten Rat Sarcoma Viral Oncogene (KRAS) is one of the most commonly mutated cancer genes in gastrointestinal cancers, especially pancreatic and colorectal cancer. For many years, KRAS was considered “undruggable,” meaning it could not be directly targeted with medications. Recently, new drugs have been developed that can block specific KRAS mutations, leading to promising results in some patients. However, responses are often temporary because tumors adapt and develop resistance. The effectiveness of KRAS-targeted therapies depends on the specific mutation, the type of cancer, and the tumor’s surrounding environment. This review explains how KRAS works, summarizes current and emerging treatments, and discusses why some therapies succeed while others fail. We highlight the importance of combining KRAS inhibitors with other treatments and tailoring therapy to the specific biology of each cancer. Continued research is needed to improve long-term outcomes for patients with KRAS-mutated gastrointestinal cancers.

KRAS-targeted therapy has opened new doors in the world of oncology, and many trials are underway for KRAS specific treatments for gastrointestinal (GI) malignancies. Outlining the current state of KRAS 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 KRAS and GI malignancies. Current therapies are discussed with an in-depth exploration of the KRAS 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 KRAS 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 KRAS inhibitors that have been successful in pre-clinical trials. More unique therapeutic options include KRAS T cell therapies, vaccines, and combination strategies with immunotherapy. Furthermore, we address the difficulties with KRAS 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 KRAS-targeted therapeutics involving GI malignancies.