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Published on: September 3, 2013
HER3 Is an Actionable Target in Advanced Prostate Cancer
Veronica Gil1, Susana Miranda1, Ruth Riisnaes1,2
1The Institute of Cancer Research, London, United Kingdom.
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.
Insights
High HER3 protein expression in lethal prostate cancer is linked to poor outcomes. Targeting HER3, activated by NRG1 from myeloid cells, shows promise for advanced prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- ERBB signaling is crucial in prostate cancer, but direct targeting of ERBB receptors has yielded limited clinical success.
- Membranous HER3 protein overexpression is frequently observed in lethal prostate cancer.
- High HER3 expression correlates with shorter time to castration resistance and reduced survival.
Purpose of the Study:
- To investigate the role of HER3 and its ligand NRG1 in prostate cancer progression and therapeutic targeting.
- To determine the cellular source of NRG1 in the prostate cancer tumor microenvironment.
- To evaluate the efficacy of HER3-targeted therapies in preclinical models.
Main Methods:
- Multiplex immunofluorescence and single-cell RNA sequencing were used to identify NRG1-producing cells.
- Prostate cancer organoid models (patient-derived and murine) were utilized to study NRG1's effect on proliferation and survival.
- In vitro experiments assessed the impact of myeloid cell-derived factors and their neutralization.
- Antitumor activity of the HER3-directed antibody-drug conjugate U3-1402 was evaluated.
Main Results:
- NRG1 was primarily detected in tumor-infiltrating myelomonocytic cells in human and murine prostate cancer.
- Recombinant NRG1 promoted proliferation and survival in HER3-expressing prostate cancer organoids.
- Myeloid cell supernatants enhanced tumor growth, which was reversed by anti-NRG1 antibodies and ERBB inhibition.
- The HER3-directed antibody-drug conjugate U3-1402 demonstrated antitumor activity in HER3-expressing prostate cancer models.
Conclusions:
- HER3 is frequently overexpressed in lethal prostate cancer and is activated by NRG1 from the tumor microenvironment's myelomonocytic cells.
- Targeting HER3, particularly with antibody-drug conjugates like U3-1402, represents a viable therapeutic strategy for advanced, HER3-expressing prostate cancer.
- Targeting HER3 warrants further clinical investigation in prospective trials for advanced prostate cancer.
