{"doi":"10.1002/cam4.413","title":"Activity of second‐generation ALK inhibitors against crizotinib‐resistant mutants in an NPM‐ALK model compared to EML4‐ALK","abstract":"<jats:title>Abstract</jats:title><jats:p>Anaplastic lymphoma kinase (<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐positive anaplastic large‐cell lymphoma (<jats:styled-content style=\"fixed-case\">ALCL</jats:styled-content>) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (<jats:styled-content style=\"fixed-case\">NPM</jats:styled-content>)‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>, whereas 5% of non‐small‐cell lung cancer (<jats:styled-content style=\"fixed-case\">NSCLC</jats:styled-content>) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule‐associated protein‐like 4 (<jats:styled-content style=\"fixed-case\">EML</jats:styled-content>4)‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> fusion. The <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>/c‐<jats:styled-content style=\"fixed-case\">MET</jats:styled-content>/<jats:styled-content style=\"fixed-case\">ROS</jats:styled-content> inhibitor crizotinib successfully improved the treatment of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐driven diseases. However, several cases of resistance appeared in <jats:styled-content style=\"fixed-case\">NSCLC</jats:styled-content> patients, and <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second‐generation <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> mutations extends beyond the specific type of fusion, both <jats:styled-content style=\"fixed-case\">NPM</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐ and <jats:styled-content style=\"fixed-case\">EML</jats:styled-content>4‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (&gt;10‐fold increased <jats:styled-content style=\"fixed-case\">IC</jats:styled-content><jats:sub>50</jats:sub> compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross‐resistance of known crizotinib‐resistant mutations against all second‐generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib‐resistance cases.</jats:p>","journal":"Cancer Medicine","year":2015,"id":638369,"datarank":0.6732954554598211,"base_score":4.48863636973214,"endowment":4.48863636973214,"self_citation_contribution":0.6732954554598211,"citation_network_contribution":0.0,"self_endowment_contribution":0.6732954554598211,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":88,"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":1657987,"name":"Monica Ceccon","orcid":null,"position":1,"is_corresponding":false},{"id":14297,"name":"Carlo Gambacorti‐Passerini","orcid":"0000-0001-6058-515X","position":2,"is_corresponding":false},{"id":44792,"name":"Luca Mologni","orcid":"0000-0002-6365-5149","position":3,"is_corresponding":false},{"id":1657985,"name":"Diletta Fontana","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Activity of second‐generation ALK inhibitors against crizotinib‐resistant mutants in an NPM‐ALK model compared to EML4‐ALK","abstract":"<jats:title>Abstract</jats:title><jats:p>Anaplastic lymphoma kinase (<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐positive anaplastic large‐cell lymphoma (<jats:styled-content style=\"fixed-case\">ALCL</jats:styled-content>) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (<jats:styled-content style=\"fixed-case\">NPM</jats:styled-content>)‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>, whereas 5% of non‐small‐cell lung cancer (<jats:styled-content style=\"fixed-case\">NSCLC</jats:styled-content>) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule‐associated protein‐like 4 (<jats:styled-content style=\"fixed-case\">EML</jats:styled-content>4)‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> fusion. The <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>/c‐<jats:styled-content style=\"fixed-case\">MET</jats:styled-content>/<jats:styled-content style=\"fixed-case\">ROS</jats:styled-content> inhibitor crizotinib successfully improved the treatment of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐driven diseases. However, several cases of resistance appeared in <jats:styled-content style=\"fixed-case\">NSCLC</jats:styled-content> patients, and <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second‐generation <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of <jats:styled-content style=\"fixed-case\">ALK</jats:styled-content> mutations extends beyond the specific type of fusion, both <jats:styled-content style=\"fixed-case\">NPM</jats:styled-content>‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐ and <jats:styled-content style=\"fixed-case\">EML</jats:styled-content>4‐<jats:styled-content style=\"fixed-case\">ALK</jats:styled-content>‐positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (&gt;10‐fold increased <jats:styled-content style=\"fixed-case\">IC</jats:styled-content><jats:sub>50</jats:sub> compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross‐resistance of known crizotinib‐resistant mutations against all second‐generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib‐resistance cases.</jats:p>","is_dataset_classified":null,"base_score":4.48863636973214,"endowment":4.48863636973214,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25727400","pmcid":"PMC4529334","openalex_id":"https://openalex.org/W1970564438","authors":[],"funders":[{"funder_name":"Associazione Italiana per la Ricerca sul Cancro (AIRC)","grant_id":"AIRC 2013 IG-14249","title":null}],"total_grants":1,"fwci":9.4105,"citation_percentile":0.9859971,"influential_citations":0,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":8},{"year":2016,"count":17},{"year":2017,"count":10},{"year":2018,"count":8},{"year":2019,"count":8},{"year":2020,"count":3},{"year":2021,"count":8},{"year":2022,"count":7},{"year":2023,"count":4},{"year":2024,"count":4},{"year":2025,"count":7},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.413","host_type":"journal"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fcam4.413","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.413","host_type":"publisher"},{"url":"https://doi.org/10.1002/cam4.413","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25727400","host_type":"repository"},{"url":"http://hdl.handle.net/10281/95038","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4529334","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4529334","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4529334?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Lung Cancer Treatments and Mutations","Lymphoma Diagnosis and Treatment","Lung Cancer Research Studies"],"mesh_terms":["Crizotinib","Anaplastic Lymphoma Kinase","Animals","Humans","Mutation","Protein-Tyrosine Kinases","Pyrazoles","Pyridines","Oncogene Proteins, Fusion","Drug Resistance, Neoplasm","Inhibitory Concentration 50","Receptor Protein-Tyrosine Kinases","Cell Line, Tumor","Protein Kinase Inhibitors","Mice"],"keywords":["Crizotinib","Anaplastic lymphoma kinase","Alectinib","Ceritinib","ALK inhibitor","Cancer research","Lung cancer","Biology","Medicine","Oncology","Npm-alk","Eml4-alk","Crizotinib Resistance","G1202r"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"refseq"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T20:34:32.359144Z","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":[]}