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Ref Type Journal Article
PMID (34753775)
Authors 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, Welti J, Yuan W, de Bono J, PCF/SU2C International Prostate Cancer Dream Team
Title HER3 Is an Actionable Target in Advanced Prostate Cancer.
Journal Cancer research
Vol 81
Issue 24
Date 2021 12 15
URL
Abstract Text 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. SIGNIFICANCE: 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References