NRG1-Driven Microenvironmental Resistance to PI3K Inhibition in Prostate Cancer

Prostate cancer is driven not only by tumor genetics but also by dynamic interactions with the tumor microenvironment (TME). Although alterations in the PI3K pathway are common, especially in PTEN-deficient disease, clinical results with PI3K inhibitors, even when combined with androgen receptor (AR) blockade, have been underwhelming. New evidence suggests that resistance may be driven externally, rather than by failure to adequately inhibit the pathway itself.

A large secretome screen has identified Neuregulin 1 (NRG1), a stromal-derived factor, as a key mediator of resistance to PI3K inhibitors. NRG1 was shown to restore tumor cell survival across multiple prostate cancer models, even in the presence of enzalutamide. Importantly, it is highly expressed in the stromal compartment of most human prostate tumors, highlighting its clinical relevance.

Mechanistically, NRG1 activates HER3, which pairs with HER2 to trigger downstream signaling, including reactivation of the PI3K/AKT pathway. This effectively bypasses PI3K inhibition, allowing cancer cells to maintain growth and survival signals. Blocking this axis—through HER3 knockdown or the anti-HER3 antibody seribantumab—restores sensitivity to treatment.

In vivo, combining HER3 inhibition with enzalutamide and a PI3K inhibitor significantly improved tumor control compared to standard doublet therapy. These findings suggest that resistance is not solely tumor-intrinsic but can be driven by microenvironmental signaling that reactivates key pathways upstream.

This work provides a strong rationale for combination strategies that simultaneously target AR signaling, PI3K, and HER3. It also underscores the importance of incorporating TME-derived biomarkers, such as stromal NRG1 expression, into future trial design. Addressing these external resistance mechanisms may be essential to unlocking the full potential of targeted therapies in advanced prostate cancer.

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