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Lookup NU author(s): Dr Pasquale RescignoORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
©2021 The Authors; Published by the American Association for Cancer Research. It has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow–derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth in vitro, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody–drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC.
Author(s): Gil V, Miranda S, Riisnaes R, Gurel B, D'Ambrosio M, Vasciaveo A, Crespo M, Ferreira A, Brina D, Troiani M, Sharp A, Sheehan B, Christova R, Seed G, Figueiredo I, Lambros M, Dolling D, Rekowski J, Alajati A, Clarke M, Pereira R, Flohr P, Fowler G, Boysen G, Sumanasuriya S, Bianchini D, Rescigno P, Aversa C, Tunariu N, Guo C, Paschalis A, Bertan C, Buroni L, Ning J, Carreira S, Workman P, Swain A, Califano A, Shen MM, Alimonti A, Neeb A, Yuan W, de Bono J
Publication type: Article
Publication status: Published
Journal: Cancer Research
Year: 2021
Volume: 81
Issue: 24
Pages: 6207-6218
Print publication date: 15/12/2021
Online publication date: 15/12/2021
Acceptance date: 25/10/2021
Date deposited: 06/11/2024
ISSN (print): 0008-5472
ISSN (electronic): 1538-7445
Publisher: American Association for Cancer Research Inc.
URL: https://doi.org/10.1158/0008-5472.CAN-21-3360
DOI: 10.1158/0008-5472.CAN-21-3360
PubMed id: 34753775
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