Kras Mutations in Colorectal Cancer: Impacts on Tumor Microenvironment and Therapeutic Implications Publisher



Emami A¹ ; Mahdavi Sharif P¹ ; Rezaei N^{2, 3}
Source: Expert Opinion on Therapeutic Targets Published:2025

Abstract

Introduction: Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances in immunotherapies and targeted therapies benefit a subset of CRC patients, with sub-optimal outcomes. Hence, there is an unmet need to design and manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly in pancreatic adenocarcinoma, non-small cell lung cancer, and CRC, is an on-off switch and governs several fundamental cell signaling cascades. KRAS mutations not only propel the progression and metastasis of CRC but also critically modulate responses to targeted therapies. Areas covered: We discuss the impacts of KRAS mutations on the CRC’s tumor microenvironment and describe novel strategies for targeting KRAS and its associated signaling cascades and mechanisms of drug resistance. Expert opinion: Drug development against KRAS mutations has been challenging, mainly due to structural properties (offering no appropriate binding site for small molecules), critical functions of the wild-type KRAS in non-cancerous cells, and the complex network of its downstream effector pathways (allowing malignant cells to develop resistance). Pre-clinical and early clinical data offer promises for combining KRAS inhibitors with immunotherapies and targeted therapies. © 2025 Informa UK Limited, trading as Taylor & Francis Group.