HER3 Is an Actionable Target in Advanced Prostate Cancer.
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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,
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,
Document Type
Journal Article
Date
2021-12-15
Date Accepted
2021-10-25
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. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.
Citation
Cancer research, 2021, 81 (24), pp. 6207 - 6218
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
1538-7445
1538-7445
Collections
Research Team
Signal Transduction & Molecular Pharmacology
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics