Most metabolically targeted approaches to cancer therapy have focused on the reliance
of cancer cells on glycolysis for energy metabolism. The Warburg effect is thought
to minimize the role of mitochondrial metabolism in the survival of cancer cells.
We recently demonstrated that BCR-ABL-driven leukemic cells become reliant on the
TCA cycle for energy production upon inhibition of the dominant tyrosine kinase (TK)
[1]. While normally relatively dispensable in these leukemia cells, carbon entry into
the mitochondria via pyruvate dehydrogenase becomes critical for energy homeostasis
and survival following TK inhibition. Similarly, Zhao et al. demonstrated that HIF1α-mediated
acquired resistance to TK inhibition in BCR-ABL-dependent leukemias engenders enhanced
sensitivity to oxythiamine, an inhibitor of both the pyruvate dehydrogenase complex
and the non-oxidative pentose phosphate pathway enzyme transketolase [2]. Furthermore,
inhibition of the driving oncogenic kinase, BRAF, in melanoma led to increased expression
of TCA cycle enzymes as well as oxidative phosphorylation and ATP synthesis genes,
revealing a previously unappreciated mechanism of survival in these cells via increased
flux through the TCA cycle [3].
In addition, Kluza et al. profiled the activity of enzymes in the electron transport
chain (ETC) in human and mouse BCR-ABL cell lines harboring resistance to the BCR-ABL
kinase inhibitor imatinib mesylate (IM) and found that IM-resistant cells had a reduction
in Complex I, II and IV activity, which correlated with the protein expression of
the different components [4]. This resistance came with a cost – increased reactive
oxygen species (ROS) levels and heightened sensitivity to pro-oxidants. Inhibition
of glycolysis in these IM-resistant leukemias leads to derepression of mitochondrial
respiration, increased flux through the TCA cycle, and reduced levels of ROS [4].
Thus, either inhibition of a driving TK or the development of TK resistance can alter
the dependence of leukemia cells on mitochondrial carbon use, engendering new metabolic
vulnerabilities.
Furthermore, we have demonstrated that the altered mitochondrial dependencies following
inhibition of the dominant TK extend beyond mitochondrial carbon flux and respiration.
Inhibition of the driving TK in leukemia cells (using IM or dasatinib in BCR-ABL-driven
leukemias, quizartinib in FLT3-driven leukemia, and IM in KIT-driven leukemia) makes
these cells exquisitely sensitive to low doses of oligomycin-A, an inhibitor of mitochondrial
ATP synthase, highlighting particular druggable dependencies in leukemic cells that
are exposed to TK inhibition [1]. Interestingly, these low nmol/L doses of oligomycin-A
do not inhibit oxygen consumption, a readout of ETC function, but rather lead to transient
decreases in ATP levels and changes in mitochondrial membrane potential (Ψm). Interestingly,
three additional groups have used large-scale proteomic and/or transcriptomic analyses
to identify pathways that are altered upon inhibition of a dominant oncogene. They
identified subpopulations of tumor cells in melanoma and pancreatic adeno-carcinoma
that, upon treatment with cytotoxic drugs, inhibition of the driving oncogene or withdrawal
of the dominant oncogene, upregulate components involved in the ETC and oxidative
phosphorylation [3, 5, 6]. Two of these groups used low doses of oligomycin-A, in
combination with cisplatin or KRAS-withdrawal, to target surviving cancer cells, leading
to long-term reductions in clonogenic activity. While these authors concluded that
oncogene inhibition restored dependence on mitochondrial respiration, the doses of
oligomycin-A that showed efficacy are below those capable of inhibiting respiration.
That inhibition of mitochondrial respiration is not required for the anti-cancer efficacy
of oligomycin-A may underlie its effectiveness and lack of toxicity in mouse models
[1], and furthermore, may allow its utilization in humans. In essence, inhibition
of the driving oncogene in some cancers appears to generate a therapeutic window for
oligomycin-A mediated impairment of some mitochondrial function.
In pancreatic adenocarcinoma cells, ablation of KRAS caused hyperpolarization of the
mitochondrial membrane and increased ROS production [6]. This phenotype is consistent
with increased supply of electron donors to the ETC, leading to increased generation
of ROS. Our study shows that the ability of oligomycin-A to synergize with TK inhibition
in the elimination of leukemia cells relies on the TK-mediated inhibition of glycolysis,
is partially dependent on the generation of ROS, and coincides with reduced Ψm [1].
Thus, while inhibition of mitochondrial respiration does not appear to underlie the
anti-cancer potential of oligomycin-A, some yet to be defined mitochondrial function
appears to be key.
These studies highlight a potential ubiquitous vulnerability of tumor cells that survive
both targeted and genotoxic therapies, sensitivity to mitochondrial perturbations,
that could provide a “second hit” to target quiescent or dormant cancer cells. The
biochemical nature of this vulnerability needs to be more fully defined. Nonetheless,
it could provide the lethal blow to cancers for which targeted therapies have proven
insufficient to eliminate the malignancy and in slow-cycling cancer cell subpopulations
that are inherently resistant to genotoxic and radiation-based therapies geared towards
rapidly dividing cells [5].