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HER3 Is an Actionable Target in Advanced Prostate Cancer
Veronica Gil1, Susana Miranda1, Ruth Riisnaes1,2
1The Institute of Cancer Research, London, United Kingdom.
Cancer Research
|November 10, 2021
Summary
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.
