Hypoxia-Driven Mechanisms of Drug Resistance in Prostate Cancer

TL;DR

This paper reviews how low oxygen levels in prostate cancer tumors lead to drug resistance and poor treatment outcomes.

Contribution

The paper synthesizes current evidence on hypoxia's role in prostate cancer drug resistance and its temporal patterns.

Findings

Hypoxia is a universal feature of prostate cancer and contributes to drug resistance.

Different hypoxia patterns (acute, cyclic, chronic) trigger unique tumor adaptations.

Hypoxia remains a major untargeted obstacle in prostate cancer treatment.

Abstract

Hypoxia, or low oxygen, is a hallmark of solid tumor biology that is associated with drug resistance and poor prognosis. This is particularly true for prostate cancer, which is exposed to hypoxia at inception and throughout the course of disease progression. Despite the established role of hypoxia as a major mediator of drug resistance in prostate cancer, 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 provides an overview of the mechanisms that drive hypoxia-mediated 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.

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