Prostate cancer remains a major cause of mortality, primarily owing to its progression toward treatment-resistant metastatic disease. Androgen deprivation therapies (ADT) have improved disease management, but the vast majority of tumors eventually develop resistance, most often associated with alterations in the androgen receptor and apoptotic pathways. Among the mechanisms that escape this hormonal control is the emergence of a neuroendocrine variant (NEPC), a multiresistant form that is particularly difficult to treat in the clinic. This neuroendocrine phenotype, linked to drug resistance, is characterized by reduced expression or activity of the androgen receptor, low expression of androgen-dependent genes such as PSA, and overexpression of neuroendocrine markers. Understanding the process of neuroendocrine differentiation (NED) at the molecular level is therefore essential to design strategies capable of preventing this multidrug resistance.
To identify the players involved in this transition, the authors combined RNA expression profiling and immunohistochemistry to characterize a gene signature associated with the emergence of NED in a large patient cohort: 169 cases of hormone-naïve prostate cancer and 48 cases of castration-resistant cancer. In vitro NED models and in vivo preclinical models were then used to explore the underlying cellular mechanisms and to characterize the effects of castration on tumor progression.
This work establishes for the first time that Neuropilin-1 (NRP1) is a key component of the neuroendocrine differentiation of prostate cells. NRP1 expression increases in response to androgen deprivation therapies and promotes cell survival through induction of the protein kinase C (PKC) pathway. Conversely, reducing NRP1 protein expression or PKC activation suppresses neuroendocrine differentiation, prevents tumor evolution toward castration resistance, and, in in vivo preclinical models, enhances the efficacy of docetaxel-based chemotherapy.
Taken together, these findings identify the NRP1/PKC axis as a potential therapeutic target for preventing the emergence of castration-resistant neuroendocrine variants, and position NRP1 as an early biomarker of this transition. These conclusions are situated in a context in which prolonged anti-androgen treatment fosters a lineage crisis conducive to the emergence of resistant cancers, underscoring the value of intervening upstream of the phenotypic switch. The identification of a molecular player that can be targeted from the earliest stages of neuroendocrine differentiation thus provides a useful landmark, both for patient stratification and for the development of approaches aimed at delaying the establishment of multidrug resistance.