{"doi":"10.1158/1078-0432.c.6529985","title":"Data from Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes","abstract":"<div>AbstractPurpose:<p>Approved therapies for <i>EGFR</i> exon 20, <i>ERBB2</i> mutations, and <i>NRG1</i> fusions are currently lacking for non–small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR.</p>Experimental Design:<p>Novel and existing patient-derived cell lines and xenografts harboring <i>EGFR</i> exon 20 insertion mutations, <i>ERBB2</i> mutations and amplification, and <i>NRG1</i> fusions were tested <i>in vitro</i> and <i>in vivo</i> with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling.</p>Results:<p>Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models <i>in vitro</i> by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. <i>In vivo</i>, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an <i>ERBB2</i> exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib.</p>Conclusions:<p>Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.</p></div>","journal":null,"year":2023,"id":405219,"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":0.924,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":297827,"name":"Anh T. Le","orcid":"0000-0003-4221-0914","position":1,"is_corresponding":false},{"id":297828,"name":"Andrea E. Doak","orcid":"0000-0002-7325-6889","position":2,"is_corresponding":false},{"id":297829,"name":"Vijaya G. Tirunagaru","orcid":"0000-0002-6505-8858","position":3,"is_corresponding":false},{"id":297830,"name":"Shevan Silva","orcid":"0000-0002-9942-1897","position":4,"is_corresponding":false},{"id":297831,"name":"Matthew R. Bull","orcid":"0000-0002-9388-0021","position":5,"is_corresponding":false},{"id":300017,"name":"Jeff B. Smaill","orcid":null,"position":6,"is_corresponding":false},{"id":297832,"name":"Adam V. Patterson","orcid":"0000-0001-5138-1227","position":7,"is_corresponding":false},{"id":250440,"name":"Chul Kim","orcid":"0000-0003-0191-8684","position":8,"is_corresponding":false},{"id":297833,"name":"Stephen V. Liu","orcid":"0000-0002-4852-3914","position":9,"is_corresponding":false},{"id":297834,"name":"Robert C. Doebele","orcid":"0000-0001-6728-6857","position":10,"is_corresponding":false},{"id":297826,"name":"Adriana Estrada‐Bernal","orcid":"0000-0002-0555-2766","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T01:20:49.237119Z","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":[]}