{"doi":"10.1097/jto.0b013e3182021f3e","title":"The Epidermal Growth Factor Receptor-L861Q Mutation Increases Kinase Activity without Leading to Enhanced Sensitivity Toward Epidermal Growth Factor Receptor Kinase Inhibitors","abstract":"<h4>Introduction</h4>Mutations in the epidermal growth factor receptor (EGFR) kinase domain such as EGFR-L858R and EGFR-G719S have been reported to activate the kinase and also sensitize a subset of patients with non-small cell lung cancer to EGFR kinase inhibitor treatment. Nevertheless, for other common point mutations such as EGFR-L861Q, it is unclear whether and to what extent they sensitize toward gefitinib and erlotinib. Thus far, there is no reliable cellular assay to compare in a ligand-independent manner intrinsic kinase activity and drug sensitivity of the unmutated (wild type) and mutated EGFR kinase domain.<h4>Methods</h4>To overcome this obstacle, we introduced L858R, G719S, and L861Q into the backbone of EGFRvIII. EGFRvIII has a wild type-kinase domain but is activated in a ligand-independent manner through a deletion in the extracellular domain.<h4>Results</h4>Using this tool, we show that the L861Q mutation displays enhanced kinase activity and transforming potential compared with L858R, G719S, and also to the wild type-EGFR kinase domain. Interestingly, L861Q does not increase drug sensitivity toward clinically used EGFR kinase inhibitors in contrast to the L858R and G719S mutation. In addition, we demonstrate that EGFR-L861Q could be effectively inhibited with the irreversible second-generation EGFR inhibitor WZ-4002.<h4>Conclusions</h4>Thus, in the common EGFR-L861Q mutation, activation of the kinase domain is uncoupled from a sensitizing effect toward clinically approved kinase inhibitors. Therefore, patients with EGFR-L861Q may not have the same clinical benefit from gefitinib/erlotinib treatment as patients with EGFR-L858R and EGFR-G719S mutations. Treatment with irreversible second-generation kinase inhibitors such as WZ-4002 may be an attractive option in the future for patients with EGFR-L861Q.","journal":"Journal of Thoracic Oncology","year":2011,"id":2190,"datarank":3.5437200763706267,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":2.9539462314619778,"self_endowment_contribution":0.5897738449086489,"citer_contribution":2.9539462314619778,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":45,"citers_with_citation_signal":38,"citers_with_endowment":38,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0477,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2011-02-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":25399,"name":"Christian Peschel","orcid":"0000-0003-0547-2886","position":1,"is_corresponding":false},{"id":25400,"name":"Justus Duyster","orcid":"0000-0001-7325-7753","position":2,"is_corresponding":false},{"id":25398,"name":"Rama Krishna Kancha","orcid":"0000-0001-8146-1551","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}