HER3 Is an Actionable Target in Advanced Prostate Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 09, 2021
- Source ID
- 10.1158/0008-5472.can-21-3360
Entities
People
- Abdullah Alajati
- Adam Sharp
- Alec Paschalis
- Alessandro Vasciaveo
- Amanda Swain
- Ana Ferreira
- Andrea Alimonti
- Andrea Califano
- Antje Neeb
- Beshara Sheehan
- Bora Gurel
- Caterina Aversa
- Christina Guo
- Claudia Bertan
- Daniela Brina
- David Dolling
- Diletta Bianchini
- Gemma Fowler
- George Seed
- Gunther Boysen
- Ines Figueiredo
- Jan Rekowski
- Jian Ning
- Johann de Bono
- Jonathan Welti
- Lorenzo Buroni
- Mariantonietta D’ambrosio
- Martina Troiani
- Maryou Lambros
- Mateus Crespo
- Matthew Clarke
- Michael M. Shen
- Nina Tunariu
- Pasquale Rescigno
- Paul Workman
- Pcf/su2c International Prostate Cancer Dream Team
- Penny Flohr
- Rita Pereira
- Rossitza Christova
- Ruth Riisnaes
- Semini Sumanasuriya
- Susana Miranda
- Suzanne Carreira
- Veronica Gil
- Yuan Wei
Organizations
- Academy of Medical Sciences
- Cancer Research UK
- Chordoma Foundation
- Medical Research Council
- National Cancer Institute
- National Institutes of Health
- Prostate Cancer Foundation
- Prostate Cancer UK
- Stand Up to Cancer
- The Mark Foundation for Cancer Research
- United States Department of Defense
- Università della Svizzera italiana
- Wellcome Trust Centre for Mitochondrial Research