Imatinib in the Treatment of Colorectal Cancer—Molecular Targets, Preclinical Evidence and Clinical Limitations

Colorectal cancer (CRC) remains a major therapeutic challenge, despite substantial advances in molecular characterization and targeted treatment. The heterogeneity of CRC and the development of treatment resistance highlight the need for novel therapeutic strategies and rational drug repurposing approaches. Imatinib, a well-established tyrosine kinase inhibitor, exerts pharmacological activity beyond ABL1/ABL2, targeting KIT, PDGFR, DDR1, and potentially LCK, which may contribute to distinct mechanisms of CRC progression. This review examines the emerging evidence on the potential role of imatinib in CRC, including its effects on tumor-cell proliferation and survival, invasion and metastasis, extracellular-matrix remodeling, tumor–stroma interactions, treatment resistance, and immune regulation. Preclinical studies indicate promising antitumor activity in selected molecular and biological contexts, particularly in KIT-positive tumors, PDGFR-rich stroma, mesenchymal/CMS4 tumors, and models characterized by aberrant DDR1 signaling. However, clinical evidence remains limited and does not currently support imatinib as a standard treatment for unselected CRC. Biomarker-guided patient selection, rational combination strategies, and tumor microenvironment-directed approaches may enhance its therapeutic potential. Further well-designed clinical studies are required to determine whether these biological effects can translate into meaningful clinical benefit.