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Haikala, Heidi M; Lopez, Timothy; Köhler, Jens; Eser, Pinar O; Xu, Man; Zeng, Qing; Teceno, Tyler J; Ngo, Kenneth; Zhao, Yutong; Ivanova, Elena V; Bertram, Arrien A; Leeper, Brittaney A; Chambers, Emily S; Adeni, Anika E; Taus, Luke J; Kuraguchi, Mari; Kirschmeier, Paul T; Yu, Channing; Shiose, Yoshinobu; Kamai, Yasuki; Qiu, Yang; Paweletz, Cloud P; Gokhale, Prafulla C; Jänne, Pasi A
Cancer research (Chicago, Ill.), 01/2022, Volume: 82, Issue: 1Journal Article
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for -mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in -mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer. .
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