EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody–Drug Conjugate HER3–DXd
| Autor: | Man Xu, Tyler Teceno, Pasi A. Jänne, Anika E. Adeni, Paul Kirschmeier, Timothy Lopez, Jens Köhler, Emily S. Chambers, Brittaney A Leeper, Mari Kuraguchi, Elena Ivanova, Arrien A. Bertram, Cloud P. Paweletz, Yoshinobu Shiose, Yutong Zhao, C. Yu, Yasuki Kamai, Luke J. Taus, Kenneth H. Ngo, Qing Zeng, Prafulla C. Gokhale, Heidi M. Haikala, Yang Qiu, Pinar O. Eser |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Antibody-drug conjugate Immunoconjugates Receptor ErbB-3 media_common.quotation_subject Cell Cell Culture Techniques Antineoplastic Agents Apoptosis Drug resistance Mice Cell Line Tumor medicine Animals Humans Osimertinib Epidermal growth factor receptor skin and connective tissue diseases Internalization media_common biology business.industry respiratory tract diseases ErbB Receptors body regions medicine.anatomical_structure Oncology Cancer research biology.protein Antibody business Tyrosine kinase |
| Zdroj: | Cancer Research. 82:130-141 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-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 EGFR-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. See related commentary by Lim et al., p. 18 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|