Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	81	24	2021 12 15	6207-6218	Cancer Res

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