{"doi":"10.3389/fphar.2026.1782130","title":"Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects","abstract":"<jats:p>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.</jats:p>","journal":"Frontiers in Pharmacology","year":2026,"id":596773,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1256273,"name":"Yingjun Chen","orcid":"0000-0002-4784-8282","position":1,"is_corresponding":false},{"id":1528533,"name":"Mingxin Guo","orcid":null,"position":2,"is_corresponding":false},{"id":1528534,"name":"Fan Yun","orcid":null,"position":3,"is_corresponding":false},{"id":890826,"name":"Xifeng Li","orcid":"0000-0003-4393-1916","position":4,"is_corresponding":false},{"id":52440,"name":"Chen Lu","orcid":null,"position":5,"is_corresponding":false},{"id":782936,"name":"Ying Li","orcid":"0000-0002-8029-0399","position":6,"is_corresponding":false},{"id":1528535,"name":"Fuchao Li","orcid":null,"position":7,"is_corresponding":false},{"id":556378,"name":"Lei Liu","orcid":"0000-0001-7782-4559","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Research progress of small molecule protein kinase inhibitors (SMKIs) in the treatment of colorectal cancer: mechanism, application, and future prospects","abstract":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21097893","pmcid":null,"openalex_id":"https://openalex.org/W7169599780","authors":[],"funders":[],"total_grants":0,"fwci":0.0,"citation_percentile":0.87154812,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.3389/fphar.2026.1782130","host_type":"journal"},{"url":"https://doi.org/10.3389/fphar.2026.1782130","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fphar.2026.1782130/full","host_type":"publisher"},{"url":"https://doaj.org/article/206852203da448f5abc5242814594a48","host_type":"repository"}],"fields_of_study":["Colorectal Cancer Treatments and Studies","Melanoma and MAPK Pathways","Cancer Genomics and Diagnostics"],"mesh_terms":[],"keywords":["Translational research","Clinical trial","Colorectal cancer","Drug development","Disease","Small molecule","Drug resistance","Drug discovery","Kinase"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-28T11:14:20.249387Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}