Anti-EGFR VHH-armed death receptor ligand–engineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbereabe8671
JournalScience Advances
Volume7
Issue number10
DOIs
Publication statusPublished - 2021 Mar 3

ASJC Scopus subject areas

  • General

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