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Figure S4 from HER3 Is an Actionable Target in Advanced Prostate Cancer

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posted on 2023-04-10, 16:40 authored by Veronica Gil, Susana Miranda, Ruth Riisnaes, Bora Gurel, Mariantonietta D’Ambrosio, Alessandro Vasciaveo, Mateus Crespo, Ana Ferreira, Daniela Brina, Martina Troiani, Adam Sharp, Beshara Sheehan, Rossitza Christova, George Seed, Ines Figueiredo, Maryou Lambros, David Dolling, Jan Rekowski, Abdullah Alajati, Matthew Clarke, Rita Pereira, Penny Flohr, Gemma Fowler, Gunther Boysen, Semini Sumanasuriya, Diletta Bianchini, Pasquale Rescigno, Caterina Aversa, Nina Tunariu, Christina Guo, Alec Paschalis, Claudia Bertan, Lorenzo Buroni, Jian Ning, Suzanne Carreira, Paul Workman, Amanda Swain, Andrea Califano, Michael M. Shen, Andrea Alimonti, Antje Neeb, Jonathan Welti, Wei Yuan, Johann de Bono

Supplementary Figure S4

Funding

Prostate Cancer UK

U.S. Department of Defense (DOD)

Prostate Cancer Foundation (PCF)

Stand Up To Cancer (SU2C)

Cancer Research UK (CRUK)

Imperial Experimental Cancer Medicine Centre (ECMC)

Cancer Research UK

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Daiichi Sankyo Company (Sankyo Company)

Medical Research Council (MRC)

Wellcome Trust Centre for Mitochondrial Research (WCMR)

Chordoma Foundation

Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)

Academy of Medical Sciences

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institutes of Health (NIH)

History

ARTICLE ABSTRACT

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. HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.

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    Cancer Research

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    cancer

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