Abstract |
Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)-mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.
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Authors | Yohei Kitamura, Nobuhiko Kanaya, Susana Moleirinho, Wanlu Du, Clemens Reinshagen, Nada Attia, Agnieszka Bronisz, Esther Revai Lechtich, Hikaru Sasaki, Joana Liliana Mora, Priscilla Kaliopi Brastianos, Jefferey L Falcone, Aldebaran M Hofer, Arnaldo Franco, Khalid Shah |
Journal | Science advances
(Sci Adv)
Vol. 7
Issue 10
(03 2021)
ISSN: 2375-2548 [Electronic] United States |
PMID | 33658202
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). |
Chemical References |
- Ligands
- Receptors, Death Domain
- ErbB Receptors
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Topics |
- Animals
- Brain
(metabolism)
- Brain Neoplasms
(therapy)
- Breast Neoplasms
(pathology)
- Cell Line, Tumor
- ErbB Receptors
(genetics)
- Female
- Hematopoietic Stem Cell Transplantation
- Humans
- Ligands
- Mice
- Receptors, Death Domain
(metabolism)
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