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The impact of mitochondria on cancer treatment resistance

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Abstract

Background

The ability of cancer cells to develop treatment resistance is one of the primary factors that prevent successful treatment. Although initially thought to be dysfunctional in cancer, mitochondria are significant players that mediate treatment resistance. Literature indicates that cancer cells reutilize their mitochondria to facilitate cancer progression and treatment resistance. However, the mechanisms by which the mitochondria promote treatment resistance have not yet been fully elucidated.

Conclusions and perspectives

Here, we describe various means by which mitochondria can promote treatment resistance. For example, mutations in tricarboxylic acid (TCA) cycle enzymes, i.e., fumarate hydratase and isocitrate dehydrogenase, result in the accumulation of the oncometabolites fumarate and 2-hydroxyglutarate, respectively. These oncometabolites may promote treatment resistance by upregulating the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, inhibiting the anti-tumor immune response, or promoting angiogenesis. Furthermore, stromal cells can donate intact mitochondria to cancer cells after therapy to restore mitochondrial functionality and facilitate treatment resistance. Targeting mitochondria is, therefore, a feasible strategy that may dampen treatment resistance. Analysis of tumoral DNA may also be used to guide treatment choices. It will indicate whether enzymatic mutations are present in the TCA cycle and, if so, whether the mutations or their downstream signaling pathways can be targeted. This may improve treatment outcomes by inhibiting treatment resistance or promoting the effectiveness of anti-angiogenic agents or immunotherapy.

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  1. Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa

    Michelle van der Merwe, Gustav van Niekerk, Carla Fourie, Manisha du Plessis & Anna-Mart Engelbrecht

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van der Merwe, M., van Niekerk, G., Fourie, C. et al. The impact of mitochondria on cancer treatment resistance. Cell Oncol. 44, 983–995 (2021). https://doi.org/10.1007/s13402-021-00623-y

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