دورية أكاديمية
EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd.
| العنوان: | EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd. |
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| المؤلفون: | Haikala HM; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Lopez T; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Köhler J; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Eser PO; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Xu M; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Zeng Q; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Teceno TJ; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Ngo K; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Zhao Y; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Ivanova EV; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Bertram AA; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Leeper BA; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, Massachusetts., Chambers ES; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Adeni AE; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Taus LJ; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Kuraguchi M; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Kirschmeier PT; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Yu C; Global Oncology R&D, Daiichi Sankyo, Basking Ridge, New Jersey., Shiose Y; DS Oncology Function Biomarker and Translational Research Department, Daiichi Sankyo, Shinagawa R&D Center, Tokyo, Japan., Kamai Y; Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd., Qiu Y; Global Oncology R&D, Daiichi Sankyo, Basking Ridge, New Jersey., Paweletz CP; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Gokhale PC; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, Massachusetts., Jänne PA; Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.; Harvard Medical School, Boston, Massachusetts.; Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts. |
| المصدر: | Cancer research [Cancer Res] 2022 Jan 01; Vol. 82 (1), pp. 130-141. Date of Electronic Publication: 2021 Sep 21. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Agents/*therapeutic use , ErbB Receptors/*antagonists & inhibitors , Immunoconjugates/*metabolism , Receptor, ErbB-3/*metabolism, Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Culture Techniques ; Cell Line, Tumor ; Humans ; Mice |
| مستخلص: | 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 . (©2021 American Association for Cancer Research.) |
| التعليقات: | Comment in: Cancer Res. 2022 Jan 1;82(1):18-20. (PMID: 34983785) |
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| معلومات مُعتمدة: | R35 CA220497 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Immunoconjugates) EC 2.7.10.1 (ErbB Receptors) EC 2.7.10.1 (Receptor, ErbB-3) |
| تواريخ الأحداث: | Date Created: 20210922 Date Completed: 20220217 Latest Revision: 20220716 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8732289 |
| DOI: | 10.1158/0008-5472.CAN-21-2426 |
| PMID: | 34548332 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-21-2426 |