Attenuating adaptive VEGF-A and IL-8 signaling restores durable tumor control in AR-antagonist-treated prostate cancers
Maxwell PJ., McKechnie M., Armstrong CW., Manley JM., Ong CW., Worthington J., Mills IG., Longley DB., Quigley JP., Zoubedi A., de Bono JS., Deryugina E., LaBonte MJ., Waugh DJJ.
Inhibiting androgen-signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumour microenvironment, will extend the clinical benefit of AR-targeted therapy. Here we show the ASI Enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to Enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR-expression in CD34+ vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVEC in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged Enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Co-inhibition of IL-8 and VEGF-A restored tumor-response in the presence of Enzalutamide, confirming the functional importance of their elevated expression in Enzalutamide-resistant (EnzR)-models. Moreover, co-inhibition of IL-8 and VEGF-A resulted in a durable, effective resolution of Enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia induced factors, IL-8 and VEGF-A, prolongs tumor sensitivity to Enzalutamide in pre-clinical models and may delay the onset of Enzalutamide-resistance. Implications: Targeting hypoxia induced signaling may extend the therapeutic benefit of Enzalutamide, providing an improved treatment strategy for patients with resistant disease.