{"doi":"10.1038/s41388-025-03472-3","title":"Colon cancer cells evade drug action by enhancing drug metabolism","abstract":"Abstract Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. One key reason is the lack of durable therapies that target KRAS-dependent disease, which represents approximately 40% of CRC cases. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway—a toxin clearance pathway that impacts most drugs—as upregulated in trametinib-resistant RAS/APC/P53 (“ RAP ”) tumours compared to trametinib-sensitive Ras G12V single mutant tumours. Genetic inhibition of different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib; conversely, elevating glucuronidation pathway activity was sufficient to direct trametinib resistance in Ras G12V animals. Mechanistically, pairing oncogenic RAS with hyperactive WNT activity strongly elevated PI3K/AKT/GLUT signalling, which in turn directed elevated glucose uptake and glucuronidation; our data also implicate the pentose phosphate pathway in this process. We provide evidence that this mechanism of trametinib resistance is conserved in a KRAS/APC/TP53 mouse CRC tumour organoid model. Finally, we identify two clinically accessible approaches to inhibiting drug glucuronidation: (i) blocking an initial HDAC1-mediated deacetylation step of trametinib with the FDA-approved drug vorinostat; (ii) reducing blood glucose by the alpha-glucosidase inhibitor acarbose. Overall, our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC and provides a practical path towards abrogating drug resistance in CRC tumours.","journal":"Oncogene","year":2025,"id":521607,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9569,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1179411,"name":"Teena Thakur","orcid":"0000-0003-0129-7427","position":1,"is_corresponding":false},{"id":858839,"name":"Alejandro Huerta Uribe","orcid":"0000-0002-6452-6111","position":2,"is_corresponding":false},{"id":1168754,"name":"Evangelia Stamou","orcid":null,"position":3,"is_corresponding":false},{"id":687180,"name":"Sindhura Gopinath","orcid":null,"position":4,"is_corresponding":false},{"id":65393,"name":"Owen J. Sansom","orcid":"0000-0001-9540-3010","position":5,"is_corresponding":false},{"id":443594,"name":"Oliver D.K. Maddocks","orcid":"0000-0002-5551-9091","position":6,"is_corresponding":false},{"id":584819,"name":"Ross Cagan","orcid":"0000-0001-5297-450X","position":7,"is_corresponding":false},{"id":1168457,"name":"Bojie Cong","orcid":"0000-0003-4453-2810","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:49:44.558743Z","pmid":"40634495","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":[]}