Primary
tumors evolve metabolic mechanisms favoring glycolysis for
adenosine triphosphate (
ATP) generation and
antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of
reactive oxygen species (ROS) and/or a reduction in
antioxidant defenses may elevate oxidative stress and inhibit
tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function-selective
extracellular signal-regulated kinase-1/2 (ERK1/2) inhibitors that inhibit
cancer cells through enhanced ROS, (2) a review of the role of
mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing
tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic
melanoma and
breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and
mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic
cancer. These findings and those of others suggest that targeting a
tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and
tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in
tumor cells may be selective for
cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic
cancer.