{"doi":"10.1002/ctm2.70338","title":"Responsiveness of different MET tumour alterations to type I and type II MET inhibitors","abstract":"Abstract Background Mutations in c‐MET receptor tyrosine kinase (MET) can be primary oncogenic drivers of multiple tumour types or can be acquired as mechanisms of resistance to therapy. MET tyrosine kinase inhibitors (TKIs) are classified as type I or type II inhibitors, with the former binding to the DFG‐in, active conformation of MET, and the latter to the DFG‐out, inactive conformation of MET. Understanding how the different classes of MET TKIs impact tumours with varied MET alterations is critical to optimising treatment for patients with MET altered cancers. Here, we characterise MET mutations identified in patients’ tumours and assess responsiveness to type I and II TKIs. Methods We used structural modelling, in vitro kinase and in cell‐based assays to assess the response of MET mutations to type I and II TKIs. We then translated our pre‐clinical findings and treated patients with MET mutant tumours with selected inhibitors. Results We detected the emergence of four (three previously uncharacterised and one known) MET resistance mutations (MET G1090A , MET D1213H , MET R1227K and a MET Y1230S ) in samples from patients with multiple solid tumours, including patients who had been previously treated with type I inhibitors. In silico modelling and biochemical assays across a variety of MET alterations, including the uncharacterised MET G1090A and the MET Y1230S substitutions, demonstrated impaired binding of type I but not of type II TKIs (i.e., cabozantinib/foretinib). Applying our pre‐clinical findings, we then treated two patients (one with a non‐small‐cell lung cancer and one with a renal cell carcinoma) whose tumours harboured these previously uncharacterised MET alterations with cabozantinib, a type II MET TKI, and observed clinical responses. Conclusions Comprehensive characterisation of the sensitivity of mutations to different TKI classes in oncogenic kinases may guide clinical intervention and overcome resistance to targeted therapies in selected cases. Key points Kinase mutations in RTKs are primary or secondary drivers in multiple cancer types Some of these mutations confer resistance to type I but not to type II inhibitors in preclinical samples and in patients The biochemical characterization of mutations in oncogenic kinases based on their sensitivity to type I and type II inhibitors is crucial to inform clinical intervention","journal":"Clinical and Translational Medicine","year":2025,"id":532457,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"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":1229407,"name":"Valentina Foglizzo","orcid":"0000-0001-5059-3279","position":1,"is_corresponding":false},{"id":969989,"name":"Jason Chang","orcid":"0000-0001-5425-8750","position":2,"is_corresponding":false},{"id":15544,"name":"Natasha Rekhtman","orcid":"0000-0001-5801-3144","position":3,"is_corresponding":false},{"id":617374,"name":"Ann Elizabeth Sisk","orcid":null,"position":4,"is_corresponding":false},{"id":1359095,"name":"Jamie Gibson","orcid":"0000-0003-1135-3613","position":5,"is_corresponding":false},{"id":1414009,"name":"Lia Judka","orcid":null,"position":6,"is_corresponding":false},{"id":1414010,"name":"Kristen Clemens","orcid":null,"position":7,"is_corresponding":false},{"id":1229406,"name":"Paola Roa","orcid":"0009-0009-0788-8499","position":8,"is_corresponding":false},{"id":1229408,"name":"Shaza Ahmed","orcid":"0000-0001-5258-0586","position":9,"is_corresponding":false},{"id":1229871,"name":"Nicole V. Bremer","orcid":null,"position":10,"is_corresponding":false},{"id":1414011,"name":"Courtney Lynn Binaco","orcid":null,"position":11,"is_corresponding":false},{"id":1414012,"name":"Sherifah Kemigisha Muzungu","orcid":null,"position":12,"is_corresponding":false},{"id":1262249,"name":"Estelamari Rodríguez","orcid":"0000-0001-8132-4573","position":13,"is_corresponding":false},{"id":1414013,"name":"Madeline Merrill","orcid":null,"position":14,"is_corresponding":false},{"id":1414014,"name":"Erica Sgroe","orcid":null,"position":15,"is_corresponding":false},{"id":1252882,"name":"Matteo Repetto","orcid":"0000-0001-8478-2633","position":16,"is_corresponding":false},{"id":108796,"name":"Zsofia K. Stadler","orcid":"0000-0002-6985-2864","position":17,"is_corresponding":false},{"id":56288,"name":"Michael F. Berger","orcid":"0000-0003-3882-5000","position":18,"is_corresponding":false},{"id":235761,"name":"Helena A. Yu","orcid":"0000-0002-0377-9510","position":19,"is_corresponding":false},{"id":255860,"name":"Eneda Toska","orcid":"0000-0002-8974-9792","position":20,"is_corresponding":false},{"id":265212,"name":"Srinivasaraghavan Kannan","orcid":null,"position":21,"is_corresponding":false},{"id":262968,"name":"Chandra Verma","orcid":"0000-0003-0733-9798","position":22,"is_corresponding":false},{"id":230273,"name":"Alexander Drilon","orcid":"0000-0001-6806-9061","position":23,"is_corresponding":false},{"id":235745,"name":"Emiliano Cocco","orcid":"0000-0002-1397-2656","position":24,"is_corresponding":false},{"id":108485,"name":"Yonina R. Murciano‐Goroff","orcid":"0000-0001-9027-2891","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40437874","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":[]}