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HER3, Part of a Family of Targets, for Patients with Prostate Cancer and Other Genitourinary Malignancies

Like HER2, HER3 is a receptor tyrosine kinase that plays a key role in cell growth and survival signaling pathways. Together, along with epidermal growth factor receptor, EGFR (HER1), and HER4, they make up the EGFR family. These are all well-known targets for diseases like lung and colon cancer with EGFR, and breast and gastric cancer with HER2. In earlier articles, I’ve mentioned how important HER2 might be for urothelial bladder cancer.1,2 Similarly, HER3 has a significant role in disease progression and treatment resistance of multiple genitourinary cancers, particularly prostate cancer.3 As a result, targeting HER3 may be a fruitful therapeutic strategy.

HER3 is expressed in prostate cancer cells, and its activation can be triggered by binding with ligands such as heregulins or neuregulins.3 Upon ligand binding, HER3 forms heterodimeric complexes with other members of the EGFR family, particularly HER2.4 This dimerization leads to the activation of downstream signaling pathways, including the PI3K-AKT and MAPK pathways, which are involved in promoting cell growth, survival and resistance to therapy.5

The field has known for decades the role of the EGFR family members in castration-resistant prostate cancer. However, early clinical trials, using monoclonal antibodies and small molecules have failed to demonstrate significant antitumor activity.6,7 Unlike breast cancer, genomic aberrations in HER family members are uncommon for prostate cancer. Although we now have many novel agents that can pharmacologically target HER2, HER3, and other family members effectively with novel small molecules, bispecific antibodies, and antibody drug conjugates, efforts in prostate cancer had previously been largely abandoned. Yet, some new data may reignite interest.

There is definite crosstalk between androgen receptor signaling and the HER3 pathway. HER3 signaling can mediate resistance to hormonal therapies, and recent work has focused on the role of the HER3 ligand, NRG-1. In mouse models and prostate organoid cultures, NRG1 was found in the cancer associated fibroblast supernatant. This important substance, in the prostate cancer microenvironment, promotes resistance of tumor cells to second generation antiandrogens through the activation of HER3. In these preclinical studies, pharmacological blockade of the NRG1/HER3 axis resensitized tumors to androgen deprivation both in vitro and in vivo.8 Additionally, castration-resistant prostate cancer patients with increased tumor NRG1 activity, have an inferior response to second-generation antiandrogen therapy.

NRG1 fusions can serve as rare oncogenic drivers for various solid tumors. Zenocutuzumab is an antibody that overcomes HER3 mediated NRG1 or NRG1 fusion signaling in tumors. Specifically, it binds to HER2 and interferes with NRG1 or NRG1 fusion binding to HER3 and also HER2 with HER3 heterodimerization. Early data from 73 treated patients with various tumors, like non-small cell lung cancer, pancreatic cancer, breast cancer, cholangiocarcinoma, and colorectal cancer showed an objective response rate of 34%.9 Another study with seribantumab, a monoclonal antibody targeting HER3, presented early data from 12 treated patients with NRG1 fusions. The objective response rate was 30% in the 10 evaluable patients.10

Although the NRG1 fusion population seems to be a promising subset of patients to target, regardless of the tumor type, NRG1 fusions are a very rare event, approximating 0.2% of various solid tumor malignancies tested. As a result, finding a larger population that is driven by the NRG1/HER3 axis will be important to the long-term success of novel compounds being developed to attenuate this pathway. Hence, the prostate cancer story of cancer associated fibroblast production of NRG1 in the tumor microenvironment is promising to explore, especially in patients who do not have any other hints of downstream constitutive hyperactivity of the PI3K-AKT or MAPK pathways. Below, I highlight some trials with agents targeting HER3 in patients with genitourinary cancers.

Clinical Trials Targeting HER3 in Patients with Genitourinary Cancers

  • HMBD-001, a monoclonal antibody targeting in patients with advanced HER3 positive solid tumors, including bladder and prostate cancer (NCT05057013)
  • Zenocutuzumab, a HER2/HER3 bispecific antibody for patients with NRG1 fusion non-small lung cancer or metastatic castration-resistant prostate cancer (NCT05588609)
  • Zenocutuzumab, early access program for advanced NRG1 fusion positive solid tumors, including prostate and renal cell carcinoma (NCT04100694)
  • DB-1310, a monoclonal antibody targeting HER3, in patients advanced/metastatic solid tumors, including a cohort with metastatic castration-resistant prostate cancer (NCT05785741)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Yu EY. Is HER2 Still a Worthwhile Therapeutic Target for Urothelial Bladder Cancer? Urotoday Clinical Trials Portal; September 16, 2019.
  2. Yu EY. The Next Revelation in Prostate Cancer Therapy? Antibody Drug Conjugates. Urotoday Clinical Trials Portal; June 30, 2023.
  3. Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nature Reviews Cancer 2012; 12:553.
  4. Jathal MK, Chen L, Mudryj M, Ghosh PM. Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. Immunol Endocr Metab Agents Med Chem 2011; 11:131-49.
  5. Carpenter G. Nuclear localization and possible functions of receptor tyrosine kinases. Current Opinion in Cell Biology 2003; 15:143-8.
  6. Molife LR, et al. Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer. Future Oncol 2014; 10:219-31.
  7. de Bono JS, et al. Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 2007; 25:257-62.
  8. Zhang Z, et al. Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Cancer Cell 2020; 38:1-18.
  9. Schram AM, et al. J Clin Oncol 40, no. 16_suppl (June 1, 2022) 105-105.
  10. Carrizosa DR, et al. J Clin Oncol 40, no. 16_suppl (June 1, 2022) 3006-3006.