{"title":"HER3-targeted therapeutic antibodies and antibody–drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors","authors":"Margaret E. Larsen, Hui Lyu, Bolin Liu","doi":"10.1016/j.pccm.2022.12.001","DOIUrl":"10.1016/j.pccm.2022.12.001","url":null,"abstract":"<div><p>Human epidermal growth factor receptor 3 (HER3) is a unique member of the human epidermal growth factor receptor (HER/EGFR) family, since it has negligible kinase activity. Therefore, HER3 must interact with a kinase-proficient receptor to form a heterodimer, leading to the activation of signaling cascades. Overexpression of HER3 is observed in various human cancers, including non-small cell lung cancer (NSCLC), and correlates with poor clinical outcomes in patients. Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers. Upregulation of HER3 is frequently observed in <em>EGFR</em>-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs). Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate “bypass signaling pathways”, thereby resulting in resistance to EGFR-TKIs. To date, no HER3-targeted therapy has been approved for cancer treatment. In both preclinical and clinical studies, targeting HER3 with a blocking antibody (Ab) is the only strategy being examined. Recent evaluations of an anti-HER3 Ab-drug conjugate (ADC) show promising results in patients with EGFR-TKI-resistant NSCLC. Herein, we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs, with a focus on its dimerization partners and subsequent activation of signaling pathways. We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.</p></div>","PeriodicalId":72583,"journal":{"name":"Chinese medical journal pulmonary and critical care medicine","volume":"1 1","pages":"Pages 11-17"},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47772241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}