Overcoming cancer drug resistance by blocking the production of mitochondrial ATP that fuels drug efflux pumps

The presence of drug efflux pumps that prevent drug accumulation in chemoresistant cancer cells is a cause of cancer treatment failure. We show that these drug pumps need mitochondrial ATP as fuel and that blocking mitochondrial ATP production with novel MCJ mimetics overcomes cancer chemoresistance

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Despite the development of targeted therapies, including immunotherapies, in recent decades, chemotherapy remains the most commonly used treatment for most cancers, typically as the therapy approved as first line. Chemotherapy is also used as neoadjuvant prior to surgery, and more recently in combination with immunotherapies. However, chemotherapy treatment still faces major challenges as chemoresistance usually develops in cancer patients. In some cases, patients fail to respond to the initial chemotherapy course due to intrinsic properties of the tumor cells. In most cases, after a successful response to the initial treatment with chemotherapy, the cancer recurs following acquisition of adaptive mechanisms of chemoresistance, which can extend to families of drugs distinct from the chemotherapy used (i.e., multidrug resistance). Thus, uncovering how cancer cells acquire chemoresistance and how we can overcome chemoresistance in cancer could lead to improved efficacy of standard chemotherapeutic drugs used for the treatment of multiple cancers.

The most common mechanism for multidrug resistance in cancer is the presence in cancer cells of ATP binding cassette (ABC) transporters that mediate drug efflux out of the cancer cells, decreasing intracellular accumulation of anti-cancer drugs, and thereby preventing their anti-cancer efficacy1. Similar to water well pumps, ABC transporters are high energy demanding to pump substrates out of cells, with ATP as a source of energy. Biochemical studies have indicated that up to two ATP molecules are required to efflux one molecule of substrate2.  Despite this energy demand, little is known about how the metabolic stage of the cancer cells affects ABC transporter activity and what is the source of ATP that fuels ABC transporters in the chemoresistant cancer cells.

Although most non-malignant cells generate ATP by mitochondrial respiration using the mitochondrial electron transport chain as the engine, for decades it is believed that cancer cells use aerobic glycolysis in the cytosol as the primary pathway to obtain ATP. While historically switching to a glycolytic metabolism at the expense of mitochondrial respiration has been viewed as the key mechanism promoting cancer progression, it is now clear that mitochondria continue to play essential roles in cancer cells3. Indeed, mitochondrial respiration has been associated with increased resistance to therapy. In our recent study published as Giddings et al. https://rdcu.be/ckCle we show that chemoresistant cancer cell lines display enhanced mitochondrial ATP production rate relative to their parental chemosensitive cancer cells. Glycolytic ATP production rate however was not altered with acquisition of chemoresistance. 

We therefore investigated the source of ATP that ABC transporters use to pump out chemotherapeutic drugs (e.g. doxorubicin). Our study https://rdcu.be/ckCle revealed that ABC transporters use and depend on mitochondrial ATP as the main source of energy for drug efflux in chemoresistant cancer cells. In contrast, ATP from glycolysis is dispensable. In the presence of chemotherapeutic drugs, ABC transporters could account for 15% of total mitochondrial ATP expenditure. Our findings could explain why the correlation between the expression of these transporters and chemoresistance in cancer patients has not been clear. In addition to ABC transporter expression in cancer cells, there is a need for high mitochondrial respiration to fuel the activity of these transporters.

These finding also suggest that treatment with standard chemotherapeutic drugs and novel and safe inhibitors of mitochondrial respiration could be a new therapeutic strategy. We have previously identified MCJ (Methylation-controlled J protein, encoded by DNAJC15) as a protein localized on the inner membrane of mitochondria and that acts as an endogenous brake on mitochondrial respiration by negatively regulating Complex I of the electron transport chain4,5. Retrospective and prospective studies have shown that loss of MCJ expression in tumors correlates with chemotherapy resistance and poor prognosis in breast and ovarian cancer patients6. In addition, our in vivo studies in mouse models of mammary cancer have shown that loss of MCJ in breast cancer cells leads to chemoresistance.  In the current study https://rdcu.be/ckCle, we show that increased mitochondrial respiration in chemoresistant cancer cells is due to the lack of MCJ. Importantly, we have developed therapeutic MCJ mimetics that attenuate mitochondrial respiration and ABC transporter activity in chemoresistant cancer cells. In addition, using in vivo mouse models we show the striking efficacy of combined treatment with MCJ mimetics together with doxorubicin.

Thus, our results reveal how enhanced mitochondrial respiration in chemoresistant cancer cells promotes chemoresistance, and how to overcome resistance of cancer cells to standard chemotherapeutic drugs by providing novel therapeutics (MCJ mimetics) that interfere with mitochondrial respiration.

REFERENCES

Overcoming chemoresistance of cancer cells using MCJ mimetics

1          Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5, 219-234, doi:10.1038/nrd1984 (2006).

2          Poolman, B. et al. Functional analysis of detergent-solubilized and membrane-reconstituted ATP-binding cassette transporters. Methods Enzymol 400, 429-459, doi:10.1016/S0076-6879(05)00025-X (2005).

3          Zong, W. X., Rabinowitz, J. D. & White, E. Mitochondria and Cancer. Mol Cell 61, 667-676, doi:10.1016/j.molcel.2016.02.011 (2016).

4          Hatle, K. et al. MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations. Mol Cell Biol 33, 2302-2314, doi:MCB.00189-13 [pii]10.1128/MCB.00189-13 (2013).

5          Champagne, D. P. et al. Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus. Immunity 44, 1299-1311, doi:10.1016/j.immuni.2016.02.018 (2016).

6          Fernandez-Cabezudo, M. J. et al. Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer. JCI insight 1, doi:10.1172/jci.insight.86873 (2016).

Mercedes Rincon

Professor, University of Colorado at Anschutz Medical Campus