Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects

Abstract

Colorectal cancer (CRC) is among the most common malignancies worldwide, and advanced or metastatic disease remains difficult to treat because of tumor heterogeneity, adaptive resistance, pathway redundancy, drug-related toxicity, and limited predictive biomarkers. Small-molecule kinase inhibitors (SMKIs) provide therapeutic opportunities for selected molecular subgroups by targeting key signaling pathways, but their clinical application is still constrained by complex resistance mechanisms, off-target toxicity, and insufficient biomarker-guided stratification. This narrative review summarizes recent progress in SMKIs for CRC, including molecular targets, clinical evidence, resistance mechanisms, combination strategies, and translational directions. Emerging technologies, including multi-omics profiling, artificial intelligence-assisted drug discovery, patient-derived models, liquid biopsy, molecular imaging, multidrug delivery systems, and adaptive trial designs, can be integrated into a translational “discover–validate–monitor–adapt” workflow and may help address some current limitations in targeted drug development for CRC. Future development of SMKI-based therapy in CRC will require biomarker-guided patient selection, rational combination strategies, dynamic monitoring of resistance, and prospective validation using clinically meaningful endpoints.