HER3 Is an Actionable Target in Advanced Prostate Cancer.
HER3 Is an Actionable Target in Advanced Prostate Cancer.
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HER3是晚期前列腺癌的一个可行靶点。
DOI：
10.1158/0008-5472.can-21-3360
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发表时间：
2021-12-15
期刊：
影响因子：
11.2
通讯作者：
PCF/SU2C International Prostate Cancer Dream Team
中科院分区：
文献类型：
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作者：
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
HER 3是前列腺癌中的可操作靶标，特别是抗HER 3免疫缀合物，靶向HER 3保证在前瞻性试验中进行临床评价。几十年来，人们已经认识到ERBB信号传导在前列腺癌中是重要的，但是靶向ERBB受体作为前列腺癌的治疗策略在临床上是无效的。然而，我们在这里表明，膜HER 3蛋白通常在致死性前列腺癌中高度表达，与去势抵抗（CR）和生存时间缩短有关。多重免疫荧光表明，HER 3配体NRG 1主要在人前列腺癌的肿瘤浸润性骨髓单核细胞中可检测到;使用人前列腺癌活检和鼠转基因前列腺癌模型的单细胞RNA测序证实了这一观察结果。在去势抵抗性前列腺癌（CRPC）患者来源的具有高HER 3表达的异种移植类器官以及小鼠前列腺癌类器官中，重组NRG 1增强了增殖和存活。小鼠骨髓源性巨噬细胞和骨髓源性抑制细胞的上清液在体外促进小鼠前列腺癌类器官生长，这可以通过中和抗NRG 1抗体和ERBB抑制来逆转。靶向HER 3，特别是用HER 3导向的抗体-药物缀合物U3-1402，对表达HER 3的前列腺癌表现出抗肿瘤活性。总体而言，这些数据表明，HER 3通常在致死性前列腺癌中过表达，并且可以被肿瘤微环境中的骨髓单核细胞分泌的NRG 1激活，支持治疗HER 3表达的晚期CRPC的HER 3靶向治疗策略。HER 3是前列腺癌中的可操作靶标，特别是抗HER 3免疫缀合物，靶向HER 3保证在前瞻性试验中进行临床评价。
HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials. 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. HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.