Hypoxia-Driven Mechanisms of Drug Resistance in Prostate Cancer

Prostate cancer is the most common non-cutaneous malignancy in men and is the second leading cause of male cancer-related mortality. Unlike many cancers, prostate cancer lacks clear genetic driver mutations, suggesting that factors in the tumor microenvironment contribute to the genesis and progression of this disease. Hypoxia, or a physiological state of low oxygen, is a universal characteristic of solid tumors that enhances disease progression and therapeutic resistance. Prostate cancer develops in a hypoxic microenvironment and primarily metastasizes to bone, where oxygen availability is similarly limited. Therefore, hypoxia is a major obstacle to the effective treatment of prostate cancer across all disease stages. Clinically, hypoxia is correlated with worse patient outcomes, largely because it drives resistance to the frontline therapies used to treat both primary and metastatic prostate cancer. Despite the established role of hypoxia in prostate cancer progression and drug resistance, it has not been successfully targeted therapeutically. Emerging evidence indicates that exposure to distinct temporal patterns of hypoxia (acute, cyclic, and chronic) elicits unique cellular adaptations that dictate tumor growth and survival. This review synthesizes current evidence regarding the role of hypoxia in promoting resistance to therapy in prostate cancer.