Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment

Cell Metabolism Previews

will also most definitely stimulate the field of Cardiology (Senior Associate Editor, Clinical Emerging Risk Factors Collaboration, Kaptoge, S., of inflammation research in both cardio- Trials and News, http://www.acc.org/), Belvoir Di Angelantonio, E., Lowe, G., Pepys, M.B., Publications (Editor-in-Chief, Harvard Heart Let- Thompson, S.G., Collins, R., and Danesh, J. vascular disease and cancer, as we (2010). Lancet 375, 132–140. ter), Duke Clinical Research Institute (clinical trial continue to refine therapeutics in this steering committees), Harvard Clinical Research area that are efficacious, safe, and cost- Jonasson, L., Holm, J., Skalli, O., Gabbiani, G., and Institute (clinical trial steering committee), HMP Hansson, G.K. (1985). J. Clin. Invest. 76, 125–131. effective. Communications (Editor-in-Chief, Journal of Inva- sive Cardiology), Journal of the American College Libby, P., and Hansson, G.K. (2015). Circ. Res. CONFLICTS OF INTEREST of Cardiology (Guest Editor; Associate Editor), 116, 307–311. Population Health Research Institute (clinical trial S.V. has received research funding from, has pro- steering committee), Slack Publications (Chief Pro´ chnicki, T., and Latz, E. (2017). Cell Metab. 26 vided CME on behalf of, and/or has acted as an Medical Editor, Cardiology Today’s Intervention), , 71–93. advisor to the following: Amgen, AstraZeneca, Society of Cardiovascular Patient Care (Secre- Ridker, P.M. (2016). Circ. Res. 118, 145–156. Boehringer Ingelheim, Bristol-Myers Squibb, Eli tary/Treasurer), and WebMD (CME steering Lilly, Janssen, Merck, Mylan, Novartis, Novo Nor- committees); Other, Clinical Cardiology (Deputy Ridker, P.M., Danielson, E., Fonseca, F.A., Genest, disk, Pfizer, Sanofi, and Valeant. L.A.L. has Editor), NCDR-ACTION Registry Steering Com- J., Gotto, A.M., Jr., Kastelein, J.J., Koenig, W., mittee (Chair), and VA CART Research and Publi- received research funding from, has provided Libby, P., Lorenzatti, A.J., MacFadyen, J.G., CME on behalf of, and/or has acted as an advisor cations Committee (Chair); Research Funding, et al.; JUPITER Study Group (2008). N. Engl. J. to the following: Amgen, AstraZeneca, Bayer, Amarin, Amgen, AstraZeneca, Bristol-Myers Med. 359, 2195–2207. Boehringer Ingelheim, Eli Lilly, Esperion, GSK, Squibb, Chiesi, Eisai, Ethicon, Forest Labora- Janssen, Kowa, Merck, Novartis, Novo Nordisk, tories, Ironwood, Ischemix, Lilly, Medtronic, Ridker, P.M., Everett, B.M., Thuren, T., Mac- Regeneron, Sanofi, Servier, and The Medicines Pfizer, Roche, Sanofi Aventis, and The Medicines Fadyen, J.G., Chang, W.H., Ballantyne, C., Fon- seca, F., Nicolau, J., Koenig, W., Anker, S.D., Company. D.L.B. discloses the following relation- Company; Royalties, Elsevier (Editor, Cardiovas- et al.; CANTOS Trial Group (2017a). N. Engl. J. cular Intervention: A Companion to Braunwald’s ships: Advisory Board, Cardax, Elsevier Practice Med. 377, 1119–1131. Update Cardiology, Medscape Cardiology, and Heart Disease); Site Co-Investigator, Biotronik, Boston Scientific, and St. Jude Medical (now Regado Biosciences; Board of Directors, Boston Ridker, P.M., MacFadyen, J.G., Thuren, T., Everett, VA Research Institute and Society of Cardiovas- Abbott); Trustee, American College of Cardiology; B.M., Libby, P., and Glynn, R.J.; CANTOS Trial cular Patient Care; Chair, American Heart Associ- Unfunded Research, FlowCo, Merck, PLx Group (2017b). Lancet. Published online August ation Quality Oversight Committee; Data Moni- Pharma, and Takeda. 27, 2017. http://dx.doi.org/10.1016/S0140- 6736(17)32247-X. toring Committees, Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical REFERENCES Verma, S., Wang, C.H., Li, S.H., Dumont, A.S., Fe- Research Institute, Mayo Clinic, Mount Sinai dak, P.W., Badiwala, M.V., Dhillon, B., Weisel, School of Medicine, and Population Health Dinarello, C.A. (2010). Cancer Metastasis Rev. 29, R.D., Li, R.K., Mickle, D.A., and Stewart, D.J. Research Institute; Honoraria, American College 317–329. (2002). Circulation 106, 913–919.

Resistance Is Futile: Targeting Mitochondrial Energetics and Metabolism to Overcome Drug Resistance in Cancer Treatment

Claudie Bosc,1,2 Mary A. Selak,1,2 and Jean-Emmanuel Sarry1,2,* 1Inserm, Cancer Research Center of Toulouse, U1037, 31024 Toulouse, France 2Universite´ de Toulouse, 31300 Toulouse, France *Correspondence: [email protected] https://doi.org/10.1016/j.cmet.2017.10.013

Metabolism is a key regulator of cancer biology; however, its role in therapeutic resistance has remained largely unresolved. Several new studies disclose that mitochondrial metabolism and oxidative phosphorylation at least in part drive chemoresistance in cancer and thus have important implications for targeted and more effective chemotherapies.

Despite a complete remission following myeloid leukemia (AML), due to frequent tic resistance: drug efﬂux, detoxiﬁcation intensive treatment with chemothera- relapses caused by chemotherapy-resis- enzymes, poor accessibility of the drug peutic agents, prognosis is very poor for tant cancer clones. Many hypotheses to the microenvironment and local niche, several types of cancer, including acute have been proposed to explain therapeu- supportive effects of stromal cells and

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Figure 1. Mitochondrial Oxidative Phosphorylation Drives Resistance to Chemotherapy in Leukemia and Cancer (A) Overview of a cancer translational research methodology based on PDX models that mimic the patient disease and treatment response. (B) Mitochondrial mass, mitochondrial membrane potential, mitochondrial ATP production, mitochondrial oxygen consumption rates, Krebs cycle intermediates, mitochondrial fatty acid b-oxidation, and gene signature, all consistent with a high mitochondrial oxidative phosphorylation (OXPHOS) status, are increased or enriched in residual cells after chemotherapy in cancer and AML. (C) Some types of chemotherapy induce resistance via metabolic reprogramming toward OXPHOS. Targeting high OXPHOS activity with mitochondrial inhibitors leads to an energetic and metabolic shift toward glycolysis and sensitizes cells to chemotherapy. (D) Schematic diagram of the metabolic state of cancer cells. In responders, cancer cells predominately utilize glycolysis to produce cytosolic ATP and lactate, while non-responders rely preferentially on OXPHOS to produce energy. The in vivo protective and nutrient-supportive local niche can sustain chemoresistance by providing oxidizable substrates to fuel mitochondrial OXPHOS of cancer cells. adipocytes, and overexpression of anti- AML cells are not necessarily enriched in AML (Figure 1C) (Samudio et al., 2010; apoptotic proteins. Previous reports also immature, quiescent cells or cancer Skrtic et al., 2011; Cole et al., 2015; Farge hypothesized that resistant cancer cells stem cells. Strikingly, pre-existing and et al., 2017). Very recently, Kuntz et al. are enriched in quiescent immature can- persisting cytarabine-resistant cells dis- (2017) reached a similar conclusion. While cer stem cell populations. However, played high levels of reactive oxygen spe- new-generation tyrosine kinase inhibitor none of these approaches has led to clin- cies; showed increased mitochondrial (TKI) treatment kills differentiated cells ical improvement, and the molecular mass, oxygen consumption, and ATP and spares leukemic stem cells in BCR- mechanisms of resistance still remain production; retained active polarized Abl chronic myeloid leukemia (CML), largely unknown, especially in vivo. mitochondria; and exhibited increased these investigators demonstrated that Thus, new therapies that effectively fatty acid oxidation, consistent with high primitive CML cells rely on mitochondrial eradicate resistant and residual cells are oxidative phosphorylation (OXPHOS) sta- energetic metabolism and that targeting an urgent medical need. Failure to tus (Figure 1B) (Muus et al., 1991; Henke- mitochondrial OXPHOS with the mito- discover efﬁcient drugs that kill resistant nius et al., 2017; Farge et al., 2017). chondrial protein translation inhibitor tige- cancer cells arises from the absence of Accordingly, targeting mitochondrial cycline in association with imatinib selec- relevant in vitro and in vivo models as DNA replication or protein synthesis, tively eradicates CML stem cells. Recent well as the predominant use of cultured mitochondrial biogenesis, electron trans- work by Lee et al. (2017) shows that cell lines to perform these studies. Using fer, mitochondrial protease ClpP (which MYC and MCL1 cooperatively promote a clinically relevant chemotherapeutic interacts with respiratory chain proteins), mitochondrial OXPHOS, which in turn approach with cytarabine to treat or mitochondrial fatty acid transport and induces HIF-1a and chemotherapy resis- patient-derived xenografts (PDX) that b-oxidation induced an energetic shift to- tance of cancer stem cells in triple robustly correlates with clinical outcome ward low OXPHOS (e.g., activation of the negative breast cancer. An OXPHOS- of respective patients (Figure 1A), Farge Pasteur effect) and markedly enhanced dependent energetic status has been and colleagues have shown that residual anti-leukemic effects of cytarabine in shown to be responsible for resistance

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to oncogene ablation or induced senes- tant therapeutic implications and shows bine and other chemotherapies? Not cence, oxidative stress, radiation, and that metabolic vulnerabilities might be ex- necessarily! We propose a dynamic chemotherapeutics in many hematologi- ploited therapeutically. Canonical, com- model of response to cytarabine in vivo cal and solid tumors (Caro et al., 2012; mon, or/and specific mitochondrial mech- that supports two types of resistance Vazquez et al., 2013; Lee et al., 2017). anisms of drug resistance should be pathways: an early adaptive metabolic re- This suggests that resistance in cancer investigated in the future. Additional pre- programming, and a later path dependent is associated with a shift toward a high clinical and clinical studies are also on cancer stem-cell-based intrinsic OXPHOS status that may now be consid- needed to address several key mitochon- mechanisms of drug resistance. ered a distinctive characteristic of drug drial or OXPHOS-related questions. First, resistance in cancer, especially in the why and how does cytarabine kill glyco- ACKNOWLEDGMENTS context of a protective and nutrient-sup- lytic cells in AML? It will be important to portive local niche (Figure 1D). Thus, inhi- identify mitochondrial components con- We thank all members of the Team RESISTAML, bition of OXPHOS suppresses resistance trolling both OXPHOS and cell death that Prof. Jean-Charles Portais and his Team METAToul, to EGFRi in EGFR-driven lung adenocar- affect resistance to chemotherapies or and Prof. Martin Brand and his laboratory. This work is dedicated to Prof. Jean H. Khoury. cinoma, docetaxel in prostate cancer, targeted therapies in AML or other can- MAPKi in melanoma, and 5-fluorouracil cers. Because mitochondria are at a key in colon and Myc/PGC-1a-driven pancre- crossroad of all metabolic pathways (at REFERENCES atic cancer. Indeed, several clinical trials least for one biochemical step), it is also and patient recruiting are in progress to necessary to ask what the roles and Caro, P., Kishan, A.U., Norberg, E., Stanley, I.A., Chapuy, B., Ficarro, S.B., Polak, K., Tondera, D., exploit this scientific rationale of the mechanisms are of the metabolic reprog- Gounarides, J., Yin, H., et al. (2012). Cancer Cell metabolic synthetic lethality by examining ramming that support and maintain this 22, 547–560. the effect of conventional chemother- high OXPHOS activity and phenotype. 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