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Published in: Drugs 1/2024

18-12-2023 | Review Article

Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

Authors: Bennett A. Caughey, John H. Strickler

Published in: Drugs | Issue 1/2024

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Abstract

Kirsten rat sarcoma virus (KRAS) is one of the most important and frequently mutated oncogenes in cancer and the mutational prevalence is especially high in many gastrointestinal malignancies, including colorectal cancer and pancreatic ductal adenocarcinoma. The KRAS protein is a small GTPase that functions as an “on/off” switch to activate downstream signaling, mainly through the mitogen-activated protein kinase pathway. KRAS was previously considered undruggable because of biochemical constraints; however, recent breakthroughs have enabled the development of small-molecule inhibitors of KRAS G12C. These drugs were initially approved in lung cancer and have now shown substantial clinical activity in KRAS G12C-mutated pancreatic ductal adenocarcinoma as well as colorectal cancer when combined with anti-EGFR monoclonal antibodies. Early data are encouraging for other gastrointestinal cancers as well and many other combination strategies are being investigated. Several new KRAS G12C inhibitors and novel inhibitors of other KRAS alterations have recently entered the clinic. These molecules employ a variety of innovative mechanisms and have generated intense interest. These novel drugs are especially important as KRAS G12C is rare in gastrointestinal malignancies compared with other KRAS alterations, representing potentially groundbreaking advances. Soon, the rapidly evolving landscape of novel KRAS inhibitors may substantially shift the therapeutic landscape for gastrointestinal cancers and offer meaningful survival improvements.
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Metadata
Title
Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies
Authors
Bennett A. Caughey
John H. Strickler
Publication date
18-12-2023
Publisher
Springer International Publishing
Published in
Drugs / Issue 1/2024
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-023-01980-8

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