Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

Abstract

Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic "drivers" inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy.

Figure 1

General organization of the metabolic networks in cancer cells. The input layer's internal (oncogenic signals) and external (nutrients in the environment) signals influence the organization of metabolic pathways and thereby regulate the output layer (see text for details). The general impact of the main oncogenic signals (PI3K/Akt and MAPK pathways) on the metabolic organization of cancer cells is illustrated.

Figure 2

Schematic diagram of metabolic networks placing mitochondria at the center of anabolic and bioenergetics pathways in cancer cells. Anabolic pathways are responsible for the production of macromolecules used for growth and proliferation of cancer cells. Red lines indicate glycolysis: multisteps conversion of glucose to pyruvate and pyruvate to lactate allowing the flux of glucose intermediates to fulfill anabolic pathways such as the pentose phosphate pathway and the PHGDH/serine pathway for nucleotides, lipids, and AA biosynthesis (see text for details). The decoupling of glycolysis from mitochondria is also observed. Mitochondria participate in ATP production through oxidation of alternative substrates such as glutamine or fatty acid (FA). Furthermore, mitochondria are also involved in anabolic pathways for producing building blocks (AA, lipids). Glutamine refills TCA intermediates (anaplerosis) and can feed the reverse TCA cycle for lipid synthesis (blue arrows) (see text for details).

Figure 3

Diagram presenting the main potential mitochondrial targets for cancer treatment (see text for details).

Figure 4

Hypothetical diagram depicting roles of mitochondrial reprogramming in BRAF mutated cells when exposed to BRAF inhibitors (see text for details). Mutated BRAF melanoma mainly relies on aerobic glycolysis. Upon BRAFi exposure, glucose uptake and glycolysis are inhibited leading to ER stress and cell death by apoptosis and consequent energetic collapse (inhibition of both glycolysis and mitochondrial OXPHOS). However, there remains a subpopulation of BRAFi-tolerant cells. These cells reprogram the metabolism towards mitochondrial oxidation in order to survive and consequently this BRAFi-tolerant subpopulation of cells becomes addicted to mitochondria. These surviving cells are prone to accumulating subsequent mutations (potentially induced by mitochondrial ROS overproduction) leading to the onset of a resistant phenotype characterized by aerobic glycolysis associated with high levels of mitochondrial activity (red blot: inhibition, green blot: activation).