Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer

Background: Neuroendocrine prostate Cancer (NEPC) is an aggressive subtype of prostate Cancer with limited therapeutic options. Although cisplatin is recommended as a first-line treatment, its clinical efficacy is hindered by the rapid development of drug resistance, highlighting the urgent need for effective strategies to overcome cisplatin resistance.

Methods: We established a NEPC mouse allograft model and performed RNA Sequencing to identify genes associated with cisplatin resistance. The role of CCL5 in tumor-stromal crosstalk was investigated using immunofluorescence, ELISA assays, co-culture assays, and CCL5 knockout mice. Mechanistic studies were conducted to explore CCL5/CCR5-mediated signaling pathways. The therapeutic efficacy of cisplatin combined with maraviroc, an FDA-approved CCR5 Antagonist, was evaluated in vitro using NEPC cell lines and patient-derived organoids, and in vivo using NEPC mouse models.

Results: Here, we identify a tumor-stromal interaction mediated by the CCL5/CCR5 axis that drives cisplatin resistance in NEPC. Cisplatin-induced DNA damage promotes a cGAS-STING-dependent senescence program in cancer-associated fibroblasts (CAFs), resulting in the secretion of CCL5, a key senescence-associated secretory phenotype factor. CCL5 from CAFs binds to CCR5 on tumor cells, promoting the formation of a CCR5/β-arrestin1/p85 complex that activates the PI3K/Akt pathway. This activation enhances DNA repair, protecting tumor cells from cisplatin-induced Apoptosis. Pharmacologic inhibition of the CCL5/CCR5 pathway using maraviroc, an FDA-approved CCR5 Antagonist, sensitizes NEPC cells to cisplatin treatment and significantly prolongs survival in NEPC mouse models.

Conclusions: Our findings identify the CCL5/CCR5 axis as a key mediator of tumor-stromal crosstalk driving cisplatin resistance in NEPC. Mechanistically, CAF-derived CCL5 activates Akt signaling in tumor cells by promoting the formation of the CCR5/β-arrestin1/p85 complex. Targeting this pathway with maraviroc in combination with cisplatin offers a promising therapeutic strategy for overcoming drug resistance in NEPC.

CCL5; Cancer-associated fibroblasts; Cisplatin resistance; Maraviroc; Neuroendocrine prostate cancer.