Targeting Tumor Microenvironment–Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAFs) promotes antiandrogen resistance through HER3-AKT signaling. Here, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. Immunohistochemical analysis of radical prostatectomy specimens from prostate cancer patients treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells, and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, zenocutuzumab did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment (TME)-derived NRG1 impacts responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN-wildtype prostate cancers.