Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy

Abstract

Small-molecule inhibitors of the phosphoinositide 3-kinase (PI3K), Akt, and mTOR pathway currently in the clinic produce a paradoxical reactivation of the pathway they are intended to suppress. Furthermore, fresh experimental evidence with PI3K antagonists in melanoma, glioblastoma, and prostate cancer shows that mitochondrial metabolism drives an elaborate process of tumor adaptation culminating with drug resistance and metastatic competency. This is centered on reprogramming of mitochondrial functions to promote improved cell survival and to fuel the machinery of cell motility and invasion. Key players in these responses are molecular chaperones of the Hsp90 family compartmentalized in mitochondria, which suppress apoptosis via phosphorylation of the pore component, Cyclophilin D, and enable the subcellular repositioning of active mitochondria to membrane protrusions implicated in cell motility. An inhibitor of mitochondrial Hsp90s in preclinical development (gamitrinib) prevents adaptive mitochondrial reprogramming and shows potent antitumor activity in vitro and in vivo. Other therapeutic strategies to target mitochondria for cancer therapy include small-molecule inhibitors of mutant isocitrate dehydrogenase (IDH) IDH1 (AG-120) and IDH2 (AG-221), which opened new therapeutic prospects for patients with high-risk acute myelogenous leukemia (AML). A second approach of mitochondrial therapeutics focuses on agents that elevate toxic ROS levels from a leaky electron transport chain; nevertheless, the clinical experience with these compounds, including a quinone derivative, ARQ 501, and a copper chelator, elesclomol (STA-4783) is limited. In light of this evidence, we discuss how best to target a resurgence of mitochondrial bioenergetics for cancer therapy.

Figure 1. Molecular therapy induces adaptive mitochondrial reprogramming in cancer

Activation of the PI3K pathway leads to formation of PIP3 and recruitment of Akt to the cell membrane, where it can be phosphorylated and activated. (Left) Exposure to small molecule PI3K antagonists currently in the clinic promotes the Hsp90-dependent recruitment of active Akt2 from cytosol to mitochondria, and Akt-phosphorylation of the permeability pore component CypD resulting in apoptosis inhibition. (Right) Exposure to PI3K therapy also induces the oxidative phosphorylation-dependent redistribution of mitochondria to the cortical cytoskeleton in proximity with focal adhesion complexes implicated in cell motility, and providing an efficient, regional energy source to fuel tumor cell motility and invasion. PI3K therapy reprogramming can be blocked by combination with the mtHsp90 inhibitor Gamitrinib. ECM, extracellular matrix; ETC, electron transport chain; RTK, receptor tyrosine kinase.