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Metabolic Features of Cancer Treatment Resistance

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Metabolism in Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 207))

Abstract

A major barrier to achieving durable remission and a definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types, and independent from the therapeutic approach undertaken. In recent years, subpopulations of slow-cycling cells endowed with enhanced tumorigenic potential and multidrug resistance have been isolated in different tumors, and mounting experimental evidence suggests these resistant cells are responsible for tumor relapse. An in-depth metabolic characterization of resistant tumor stem cells revealed that they rely more on mitochondrial respiration and less on glycolysis than other tumor cells, a finding that challenges the assumption that tumors have a primarily glycolytic metabolism and defective mitochondria. The demonstration of a metabolic program in resistant tumorigenic cells that may be present in the majority of tumors has important therapeutic implications and is a critical consideration as we address the challenge of identifying new vulnerabilities that might be exploited therapeutically.

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Notes

  1. 1.

    NCI_http://www.cancer.gov What is cancer? http://www.cancer.gov/about-cancer/what-is-cancer.

  2. 2.

    Vasiliou_http://www.aldh.org ALDH.ORG. http://www.aldh.org/website/aldh/.

References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alvarez-Calderon F, Gregory MA, Pham-Danis C, DeRyckere D, Stevens BM, Zaberezhnyy V, Hill AA, Gemta L, Kumar A, Kumar V, Wempe MF, Pollyea DA, Jordan CT, Serkova NJ, Graham DK, DeGregori J (2014) Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations. Clin Cancer Res An Official J Am Assoc Cancer Res. doi:10.1158/1078-0432.CCR-14-2146

    Google Scholar 

  • Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A (2008) Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res 68(5):1485–1494. doi:10.1158/0008-5472.CAN-07-0562

    Article  CAS  PubMed  Google Scholar 

  • Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760. doi:10.1038/nature05236

    Article  CAS  PubMed  Google Scholar 

  • Bardenheuer W, Lehmberg K, Rattmann I, Brueckner A, Schneider A, Sorg UR, Seeber S, Moritz T, Flasshove M (2005) Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells. Leukemia 19(12):2281–2288. doi:10.1038/sj.leu.2403977

    Article  CAS  PubMed  Google Scholar 

  • Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ (2014) Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15(1):37–50. doi:10.1016/j.stem.2014.04.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome I, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA, Grimmond SM (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405. doi:10.1038/nature11547

    Google Scholar 

  • Binkhathlan Z, Lavasanifar A (2013) P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr Cancer Drug Targets 13(3):326–346

    Article  CAS  PubMed  Google Scholar 

  • Bouwman P, Jonkers J (2012) The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 12(9):587–598. doi:10.1038/nrc3342

    Article  CAS  PubMed  Google Scholar 

  • Brockman RW (1963) Mechanisms of resistance to anticancer agents. Adv Cancer Res 7:129–234

    Article  CAS  PubMed  Google Scholar 

  • Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048. doi:10.1038/ng1861

    Article  CAS  PubMed  Google Scholar 

  • Cavalli LR, Varella-Garcia M, Liang BC (1997) Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ Mol Biol J Am Assoc Cancer Res 8(11):1189–1198

    CAS  Google Scholar 

  • Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H, Group ALKLCS (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363(18):1734–1739. doi:10.1056/NEJMoa1007478

    Google Scholar 

  • Clarkson BD (1969) Review of recent studies of cellular proliferation in acute leukemia. Natl Cancer Inst Monogr 30:81–120

    CAS  PubMed  Google Scholar 

  • Clarkson B, Fried J, Strife A, Sakai Y, Ota K, Okita T (1970) Studies of cellular proliferation in human leukemia. 3. Behavior of leukemic cells in three adults with acute leukemia given continuous infusions of 3H-thymidine for 8 or 10 days. Cancer 25(6):1237–1260

    Article  CAS  PubMed  Google Scholar 

  • Clarkson BD, Dowling MD, Gee TS, Cunningham IB, Burchenal JH (1975) Treatment of acute leukemia in adults. Cancer 36(2):775–795

    Article  CAS  PubMed  Google Scholar 

  • Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951

    Article  CAS  PubMed  Google Scholar 

  • Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, Rakshit S, Flannagan KS, Adsay NV, Pasca di Magliano M (2012) Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 122(2):639–653. doi:10.1172/JCI59227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cros E, Jordheim L, Dumontet C, Galmarini CM (2004) Problems related to resistance to cytarabine in acute myeloid leukemia. Leuk Lymphoma 45(6):1123–1132

    Article  CAS  PubMed  Google Scholar 

  • Dalla Pozza E, Fiorini C, Dando I, Menegazzi M, Sgarbossa A, Costanzo C, Palmieri M, Donadelli M (2012) Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine. Biochim Biophys Acta 1823(10):1856–1863. doi:10.1016/j.bbamcr.2012.06.007

    Article  CAS  PubMed  Google Scholar 

  • Dando I, Fiorini C, Pozza ED, Padroni C, Costanzo C, Palmieri M, Donadelli M (2013) UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochim Biophys Acta 1833(3):672–679. doi:10.1016/j.bbamcr.2012.10.028

    Article  CAS  PubMed  Google Scholar 

  • Debenham PG, Kartner N, Siminovitch L, Riordan JR, Ling V (1982) DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression. Mol Cell Biol 2(8):881–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derdak Z, Mark NM, Beldi G, Robson SC, Wands JR, Baffy G (2008) The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells. Cancer Res 68(8):2813–2819. doi:10.1158/0008-5472.CAN-08-0053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dick JE (2008) Stem cell concepts renew cancer research. Blood 112(13):4793–4807. doi:10.1182/blood-2008-08-077941

    Article  CAS  PubMed  Google Scholar 

  • Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783. doi:10.1038/nature07733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451(7182):1111–1115. doi:10.1038/nature06548

    Article  CAS  PubMed  Google Scholar 

  • Farber S, Diamond LK (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 238(23):787–793. doi:10.1056/NEJM194806032382301

    Article  CAS  PubMed  Google Scholar 

  • Felsher DW (2008) Tumor dormancy and oncogene addiction. APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica 116(7–8):629–637. doi:10.1111/j.1600-0463.2008.01037.x

    Article  CAS  PubMed  Google Scholar 

  • Ferreira LM (2010) Cancer metabolism: the Warburg effect today. Exp Mol Pathol 89(3):372–380. doi:10.1016/j.yexmp.2010.08.006

    Article  CAS  PubMed  Google Scholar 

  • Fisher GA, Lum BL, Hausdorff J, Sikic BI (1996) Pharmacological considerations in the modulation of multidrug resistance. Eur J Cancer 32A(6):1082–1088

    Article  CAS  PubMed  Google Scholar 

  • Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819. doi:10.1056/NEJMoa1002011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frei E 3rd, Karon M, Levin RH, Freireich EJ, Taylor RJ, Hananian J, Selawry O, Holland JF, Hoogstraten B, Wolman IJ, Abir E, Sawitsky A, Lee S, Mills SD, Burgert EO Jr, Spurr CL, Patterson RB, Ebaugh FG, James GW 3rd, Moon JH (1965) The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 26(5):642–656

    PubMed  Google Scholar 

  • Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159. doi:10.1126/science.312.5777.1158

    Article  CAS  PubMed  Google Scholar 

  • Garraway LA, Chabner B (2002) MDR1 inhibition: less resistance or less relevance? Eur J Cancer 38(18):2337–2340

    Article  CAS  PubMed  Google Scholar 

  • Goodman LS, Wintrobe MM et al (1946) Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc 132:126–132

    Article  CAS  PubMed  Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531):876–880. doi:10.1126/science.1062538

    Article  CAS  PubMed  Google Scholar 

  • Gottesman MM (2002) Mechanisms of cancer drug resistance. Ann Rev Med 53:615–627. doi:10.1146/annurev.med.53.082901.103929

    Article  CAS  PubMed  Google Scholar 

  • Guan Y, Gerhard B, Hogge DE (2003) Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood 101(8):3142–3149. doi:10.1182/blood-2002-10-3062

    Article  CAS  PubMed  Google Scholar 

  • Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E (2011) Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25(5):460–470. doi:10.1101/gad.2016311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, Frederick DT, Hurley AD, Nellore A, Kung AL, Wargo JA, Song JS, Fisher DE, Arany Z, Widlund HR (2013) Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 23(3):302–315. doi:10.1016/j.ccr.2013.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi J, Takemitsu M, Nonaka I (1992) Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells. Somat Cell Mol Genet 18(2):123–129

    Article  CAS  PubMed  Google Scholar 

  • Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 101(39):14228–14233. doi:10.1073/pnas.0400067101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13(10):714–726. doi:10.1038/nrc3599

    Article  CAS  PubMed  Google Scholar 

  • Hu YL, Jahangiri A, Delay M, Aghi MK (2012) Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res 72(17):4294–4299. doi:10.1158/0008-5472.CAN-12-1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W (1991) Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res 51(22):6110–6117

    CAS  PubMed  Google Scholar 

  • Insinga A, Cicalese A, Faretta M, Gallo B, Albano L, Ronzoni S, Furia L, Viale A, Pelicci PG (2013) DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions. Proc Natl Acad Sci USA 110(10):3931–3936. doi:10.1073/pnas.1213394110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD (2007) Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25(11):1315–1321. doi:10.1038/nbt1350

    Article  CAS  PubMed  Google Scholar 

  • Jang S, Atkins MB (2013) Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol 14(2):e60–e69. doi:10.1016/S1470-2045(12)70539-9

    Article  CAS  PubMed  Google Scholar 

  • Janku F, McConkey DJ, Hong DS, Kurzrock R (2011) Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol 8(9):528–539. doi:10.1038/nrclinonc.2011.71

    Article  CAS  PubMed  Google Scholar 

  • Januchowski R, Wojtowicz K, Zabel M (2013) The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 67(7):669–680. doi:10.1016/j.biopha.2013.04.005

    Article  CAS  PubMed  Google Scholar 

  • Jose C, Bellance N, Rossignol R (2011) Choosing between glycolysis and oxidative phosphorylation: a tumor’s dilemma? Biochim Biophys Acta 1807(6):552–561. doi:10.1016/j.bbabio.2010.10.012

    Article  CAS  PubMed  Google Scholar 

  • Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E, International STICMLSG (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346(9):645–652. doi:10.1056/NEJMoa011573

    Google Scholar 

  • Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q, Zhong Y, Wu CJ, Sadanandam A, Hu B, Chang Q, Chu GC, Al-Khalil R, Jiang S, Xia H, Fletcher-Sananikone E, Lim C, Horwitz GI, Viale A, Pettazzoni P, Sanchez N, Wang H, Protopopov A, Zhang J, Heffernan T, Johnson RL, Chin L, Wang YA, Draetta G, DePinho RA (2014) Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158(1):185–197. doi:10.1016/j.cell.2014.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelley SL, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS (1988) Overexpression of metallothionein confers resistance to anticancer drugs. Science 241(4874):1813–1815

    Article  CAS  PubMed  Google Scholar 

  • Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121(6):823–835

    Article  CAS  PubMed  Google Scholar 

  • King MP, Attardi G (1989) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246(4929):500–503

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352(8):786–792. doi:10.1056/NEJMoa044238

    Article  CAS  PubMed  Google Scholar 

  • Kufe DW, Spriggs DR (1985) Biochemical and cellular pharmacology of cytosine arabinoside. Semin Oncol 12(2 Suppl 3):34–48

    CAS  PubMed  Google Scholar 

  • Kwon HC, Roh MS, Oh SY, Kim SH, Kim MC, Kim JS, Kim HJ (2007) Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol Official J Eur Soc Med Oncol/ESMO 18(3):504–509. doi:10.1093/annonc/mdl430

    Article  Google Scholar 

  • Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O’Dwyer KM, Liesveld JL, Brookes PS, Becker MW, Jordan CT (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12(3):329–341. doi:10.1016/j.stem.2012.12.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, Kalluri R (2014) PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16(10):992–1003, 1001–1015. doi:10.1038/ncb3039

    Google Scholar 

  • Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037. doi:10.1158/0008-5472.CAN-06-2030

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Schubert DR (2009) The specificity of neuroprotection by antioxidants. J Biomed Sci 16:98. doi:10.1186/1423-0127-16-98

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67. doi:10.1186/1476-4598-5-67

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB (2005) Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120(2):237–248. doi:10.1016/j.cell.2004.11.046

    Article  CAS  PubMed  Google Scholar 

  • Mailloux RJ, Adjeitey CN, Harper ME (2010) Genipin-induced inhibition of uncoupling protein-2 sensitizes drug-resistant cancer cells to cytotoxic agents. PLoS ONE 5(10):e13289. doi:10.1371/journal.pone.0013289

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mistry P, Kelland LR, Abel G, Sidhar S, Harrap KR (1991) The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines. Br J Cancer 64(2):215–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morais R, Zinkewich-Peotti K, Parent M, Wang H, Babai F, Zollinger M (1994) Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. Cancer Res 54(14):3889–3896

    CAS  PubMed  Google Scholar 

  • Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468(7326):973–977. doi:10.1038/nature09626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  CAS  Google Scholar 

  • Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC, Investigators IB (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355(10):983–991. doi:10.1056/NEJMoa060570

    Article  CAS  PubMed  Google Scholar 

  • Park D, Han CZ, Elliott MR, Kinchen JM, Trampont PC, Das S, Collins S, Lysiak JJ, Hoehn KL, Ravichandran KS (2011) Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477(7363):220–224. doi:10.1038/nature10340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 65(14):6207–6219. doi:10.1158/0008-5472.CAN-05-0592

    Article  CAS  PubMed  Google Scholar 

  • Persidis A (1999) Cancer multidrug resistance. Nat Biotechnol 17(1):94–95. doi:10.1038/5289

    Article  CAS  PubMed  Google Scholar 

  • Pettazzoni P, Viale A, Shah P, Carugo A, Ying H, Wang H, Genovese G, Seth S, Minelli R, Green T, Huang-Hobbs E, Corti D, Sanchez N, Nezi L, Marchesini M, Kapoor A, Yao W, Francesco ME, Petrocchi A, Deem AK, Scott K, Colla S, Mills GB, Fleming JB, Heffernan TP, Jones P, Toniatti C, DePinho RA, Draetta GF (2015) Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res 75(6):1091–1101. doi:10.1158/0008-5472.CAN-14-1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598. doi:10.1038/nature07567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM, Morrison SJ (2010) Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18(5):510–523. doi:10.1016/j.ccr.2010.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintas-Cardama A, Kantarjian H, Cortes J (2009) Imatinib and beyond–exploring the full potential of targeted therapy for CML. Nat Rev Clin Oncol 6(9):535–543. doi:10.1038/nrclinonc.2009.112

    Article  CAS  PubMed  Google Scholar 

  • Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330(6009):1344–1348. doi:10.1126/science.1193497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    Article  CAS  PubMed  Google Scholar 

  • Riordan JR, Deuchars K, Kartner N, Alon N, Trent J, Ling V (1985) Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature 316(6031):817–819

    Article  CAS  PubMed  Google Scholar 

  • Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A, Basu D, Gimotty P, Vogt T, Herlyn M (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141(4):583–594. doi:10.1016/j.cell.2010.04.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Korbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, Patzold S, Villanueva J, Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian BC, Vogt T, Herlyn M (2013) Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23(6):811–825. doi:10.1016/j.ccr.2013.05.003

    Article  CAS  PubMed  Google Scholar 

  • Rohlena J, Dong LF, Ralph SJ, Neuzil J (2011) Anticancer drugs targeting the mitochondrial electron transport chain. Antioxid Redox Signal 15(12):2951–2974. doi:10.1089/ars.2011.3990

    Article  CAS  PubMed  Google Scholar 

  • Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, Urban N, Taniguchi T (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451(7182):1116–1120. doi:10.1038/nature06633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scandurra FM, Gnaiger E (2010) Cell respiration under hypoxia: facts and artefacts in mitochondrial oxygen kinetics. Adv Exp Med Biol 662:7–25. doi:10.1007/978-1-4419-1241-1_2

    Article  CAS  PubMed  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    Article  CAS  PubMed  Google Scholar 

  • Skipper HE, Perry S (1970) Kinetics of normal and leukemic leukocyte populations and relevance to chemotherapy. Cancer Res 30(6):1883–1897

    CAS  PubMed  Google Scholar 

  • Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z, Hurren R, Jitkova Y, Gronda M, Maclean N, Lai CK, Eberhard Y, Bartoszko J, Spagnuolo P, Rutledge AC, Datti A, Ketela T, Moffat J, Robinson BH, Cameron JH, Wrana J, Eaves CJ, Minden MD, Wang JC, Dick JE, Humphries K, Nislow C, Giaever G, Schimmer AD (2011) Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20(5):674–688. doi:10.1016/j.ccr.2011.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H (2013) Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4:e838. doi:10.1038/cddis.2013.350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q, Hardcastle T, Lee A, Roy R, East P, Kschischo M, Endesfelder D, Wylie P, Kim SN, Chen JG, Howell M, Ried T, Habermann JK, Auer G, Brenton JD, Szallasi Z, Downward J (2009) Chromosomal instability determines taxane response. Proc Natl Acad Sci USA 106(21):8671–8676. doi:10.1073/pnas.0811835106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan AS, Baty JW, Dong LF, Bezawork-Geleta A, Endaya B, Goodwin J, Bajzikova M, Kovarova J, Peterka M, Yan B, Pesdar EA, Sobol M, Filimonenko A, Stuart S, Vondrusova M, Kluckova K, Sachaphibulkij K, Rohlena J, Hozak P, Truksa J, Eccles D, Haupt LM, Griffiths LR, Neuzil J, Berridge MV (2015) Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab 21(1):81–94. doi:10.1016/j.cmet.2014.12.003

    Article  CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi:10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, Puigserver P (2013) PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23(3):287–301. doi:10.1016/j.ccr.2012.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viale A, De Franco F, Orleth A, Cambiaghi V, Giuliani V, Bossi D, Ronchini C, Ronzoni S, Muradore I, Monestiroli S, Gobbi A, Alcalay M, Minucci S, Pelicci PG (2009) Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457(7225):51–56. doi:10.1038/nature07618

    Article  CAS  PubMed  Google Scholar 

  • Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, Draetta GF (2014) Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514(7524):628–632. doi:10.1038/nature13611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, Kehoe SM, Johannessen CM, Macconaill LE, Hahn WC, Meyerson M, Garraway LA (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol Official J Am Soc Clin Oncol 29(22):3085–3096. doi:10.1200/JCO.2010.33.2312

    Article  CAS  Google Scholar 

  • Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12(10):685–698. doi:10.1038/nrc3365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Guo LP, Chen LZ, Zeng YX, Lu SH (2007) Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 67(8):3716–3724. doi:10.1158/0008-5472.CAN-06-4343

    Article  CAS  PubMed  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  CAS  PubMed  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8(6):519–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinstein IB (2002) Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science 297(5578):63–64. doi:10.1126/science.1073096

    Article  CAS  PubMed  Google Scholar 

  • Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction–a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3(8):448–457. doi:10.1038/ncponc0558

    Article  CAS  PubMed  Google Scholar 

  • Wilson TR, Longley DB, Johnston PG (2006) Chemoresistance in solid tumours. Ann Oncol Official J Eur Soc Med Oncol/ESMO 17(Suppl 10):x315–x324. doi:10.1093/annonc/mdl280

    Article  Google Scholar 

  • Wolf DA (2014) Is reliance on mitochondrial respiration a “chink in the armor” of therapy-resistant cancer? Cancer Cell 26(6):788–795. doi:10.1016/j.ccell.2014.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC (2011) Pancreatic cancers require autophagy for tumor growth. Genes Dev 25(7):717–729. doi:10.1101/gad.2016111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, DePinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149(3):656–670. doi:10.1016/j.cell.2012.01.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zahreddine H, Borden KL (2013) Mechanisms and insights into drug resistance in cancer. Front Pharmacol 4:28. doi:10.3389/fphar.2013.00028

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7(9):1028–1034. doi:10.1038/nm0901-1028

    Article  CAS  PubMed  Google Scholar 

  • Zhou W, Yang Y, Xia J, Wang H, Salama ME, Xiong W, Xu H, Shetty S, Chen T, Zeng Z, Shi L, Zangari M, Miles R, Bearss D, Tricot G, Zhan F (2013) NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell 23(1):48–62. doi:10.1016/j.ccr.2012.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zu XL, Guppy M (2004) Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313(3):459–465

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Authors are thankful to Angela K. Deem for editing the manuscript and apologize for the omission of any primary references.

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Authors and Affiliations

  1. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Andrea Viale & Giulio F. Draetta

  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Giulio F. Draetta

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  1. Andrea Viale
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Correspondence to Andrea Viale .

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Editors and Affiliations

  1. RWTH University Hospital, Molecular Tumor Biology, Pauwelsstrasse 30, 52074 , Aachen, Germany

    Thorsten Cramer

  2. Dept. of Hematology and Oncology, Charité, Berlin, Germany

    Clemens A. Schmitt

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Viale, A., Draetta, G.F. (2016). Metabolic Features of Cancer Treatment Resistance. In: Cramer, T., A. Schmitt, C. (eds) Metabolism in Cancer. Recent Results in Cancer Research, vol 207. Springer, Cham. https://doi.org/10.1007/978-3-319-42118-6_6

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