Exploiting Cancer Cells Metabolic Adaptability to Enhance Therapy Response in Cancer

  • Sofia C. Nunes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1219)


Despite all the progresses developed in prevention and new treatment approaches, cancer is the second leading cause of death worldwide, being chemoresistance a pivotal barrier in cancer management. Cancer cells present several mechanisms of drug resistance/tolerance and recently, growing evidence have been supporting a role of metabolism reprograming per se as a driver of chemoresistance. In fact, cancer cells display several adaptive mechanisms that allow the emergency of chemoresistance, revealing cancer as a disease that adapts and evolve along with the treatment. Therefore, clinical protocols that take into account the adaptive potential of cancer cells should be more effective than the current traditional standard protocols on the fighting against cancer.

In here, some of the recent findings on the role of metabolism reprograming in cancer chemoresistance emergence will be discussed, as the potential evolutionary strategies that could unable these adaptations, hence allowing to prevent the emergency of treatment resistance, changing cancer outcome.


Adaptation Cancer Chemoresistance Evolution Metabolism 



The authors acknowledge iNOVA4Health – UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement.


  1. Ahmed N, Escalona R, Leung D, Chan E, Kannourakis G (2018) Tumour microenvironment and metabolic plasticity in cancer and cancer stem cells: perspectives on metabolic and immune regulatory signatures in chemoresistant ovarian cancer stem cells. Semin Cancer Biol 53:265–281. Scholar
  2. Aktipis CA, Kwan VSY, Johnson KA, Neuberg SL, Maley CC (2011) Overlooking evolution: a systematic analysis of cancer relapse and therapeutic resistance research. PLoS One 6:e26100.1–e26100.9. Scholar
  3. Alam MM, Lal S, FitzGerald KE, Zhang L (2016) A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors. Clin Transl Med 5(3).
  4. Allen E, Ville PM, Warren CM, Saghafinia S, Li L, Peng MW, Hanahan D (2016) Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling. Cell Rep 15:1144–1160. Scholar
  5. Axelrod R, Axelrod DE, Pienta KJ (2006) Evolution of cooperation among tumor cells. Proc Natl Acad Sci U S A 103:13474–13479. Scholar
  6. Cairns J (1975) Mutation selection and the natural history of cancer. Nature 255:197–200. (2018)CrossRefPubMedGoogle Scholar
  7. Crespi B, Summers K (2005) Evolutionary biology of cancer. Trends Ecol Evol 20:545–552. Scholar
  8. Dar S, Chhina J, Mert I, Chitale D, Buekers T, Kaur H et al (2017) Bioenergetic adaptations in chemoresistant ovarian cancer cells. Sci Rep 7:1–17. Scholar
  9. Datta S, Choudhury D, Das A, Das Mukherjee D, Das N, Roy SS, Chakrabarti G (2017) Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: a chronological study. Tumor Biol 39:1–14. Scholar
  10. Deblois G, Tonekaboni SAM, Kao YI, Tai F, Liu X, Ettayebi I et al (2018) Metabolic adaptations underlie epigenetic vulnerabilities in chemoresistant breast cancer. bioRxiv:1–51.
  11. Denise C, Paoli P, Calvani M, Taddei ML, Giannoni E, Kopetz S et al (2015) 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget 6:41706–41721. Scholar
  12. Enriquez-navas PM, and Gatenby RA (2017) Applying tools from evolutionary biology to cancer research. Ecol Evol Cancer. Chapter 14:193–200.
  13. Enriquez-navas PM, Wojtkowiak JW, Gatenby RA (2015) Application of evolutionary principles to cancer therapy. Cancer Res 75:4675–4680. Scholar
  14. Enriquez-Navas PM, Kam Y, Das T, Hassan S, Silva A, Foroutan P et al (2016) Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer. Sci Transl Med 8:1–9. Scholar
  15. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C et al. (2013a) GLOBOCAN 2012a v1.0, cancer incidence and mortality worldwide: IARC cancerbase No. 11. Retrieved August 24, 2018, from
  16. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C et al. (2013b) GLOBOCAN 2012b v1.0, cancer incidence and mortality worldwide: IARC cancerbase no. 11. Retrieved August 30, 2018, from
  17. Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF et al (2015) The global burden of cancer 2013. JAMA Oncol 1:505–527. Scholar
  18. Gallaher JA, Enriquez-Navas PM, Luddy KA, Gatenby RA, Anderson ARA (2017) Spatial heterogeneity and evolutionary dynamics modulate time to recurrence in continuous and adaptive cancer therapies. bioRxiv:1–21.
  19. Gallipoli P, Giotopoulos G, Tzelepis K, Costa ASH, Vohra S, Medina-Perez P et al (2018) Glutaminolysis is a metabolic dependency in FLT3ITDacute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. Blood 131:1639–1653. Scholar
  20. Gastel N, van Schajnovitz A, Vidoudez C, Oki T, Sharda A, Trauger SA, Scadden DT (2017) Untargeted metabolomics identifies glutamine metabolism as a driver of chemoresistance in acute myeloid Leukemia. Blood 130:2523Google Scholar
  21. Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69:4894–4903. Scholar
  22. Gillies RJ, Verduzco D, Gatenby RA (2012) Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer 12:487–493. Scholar
  23. Goldman A, Majumder B, Dhawan A, Ravi S, Goldman D, Kohandel M et al (2015) Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition. Nat Commun 6:1–13. Scholar
  24. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627. Scholar
  25. Guppy M, Leedman P, Zu X, Russell V (2002) Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364:309–315. Scholar
  26. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70. Scholar
  27. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. Scholar
  28. Hayes JD, Dinkova-Kostova AT (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39:199–218. Scholar
  29. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726. Scholar
  30. Ippolito L, Marini A, Cavallini L, Morandi A, Pietrovito L, Pintus G et al (2016) Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells. Oncotarget 7:61890–61904. Scholar
  31. Jia D, Park J, Jung K, Levine H, Kaipparettu B (2018) Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cell 7:21. Scholar
  32. Ju HQ, Gocho T, Aguilar M, Wu M, Zhuang ZN, Fu J et al (2015) Mechanisms of overcoming intrinsic resistance to gemcitabine in pancreatic ductal adenocarcinoma through the redox modulation. Mol Cancer Ther 14:788–798. Scholar
  33. Kent DG, Green AR (2017) Order matters: the order of somatic mutations influences cancer evolution. Cold Spring Harb Perspect Med 7:1–16. Scholar
  34. Kerr EM, Gaude E, Turrell FK, Frezza C, Martins CP (2016) Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature 531:110–113. Scholar
  35. Khamari R, Trinh A, Gabert PE, Corazao-Rozas P, Riveros-Cruz S, Balayssac S et al (2018) Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors. Cell Death Dis 9:325–338. Scholar
  36. Komurov K, Tseng JT, Muller M, Seviour EG, Moss TJ, Yang L et al (2012) The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ErbB2-positive breast cancer cells. Mol Syst Biol 8:1–10. Scholar
  37. Kong X, Kuilman T, Shahrabi A, Boshuizen J, Kemper K, Song JY et al (2017) Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature 550:270–274. Scholar
  38. Landriscina M, Maddalena F, Laudiero G, Esposito F (2009) Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid Redox Signal 11:2701–2716. Scholar
  39. Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W et al (2017) ARF6, induced by mutant Kras, promotes proliferation and Warburg effect in pancreatic cancer. Cancer Lett 388:303–311. Scholar
  40. Liberti MV, Locasale JW (2016) The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci 41:211–218. Scholar
  41. Liu T, Yin H (2017) PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncol Rep 37:193–200. Scholar
  42. Liu Y, Cao Y, Pan X, Shi M, Wu Q, Huang T et al (2018) O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance. Cell Death Dis 9:485–496. Scholar
  43. Lopes-Coelho F, Nunes C, Gouveia-Fernandes S, Rosas R, Silva F, Gameiro P et al (2017) Monocarboxylate transporter 1 (MCT1), a tool to stratify acute myeloid leukemia (AML) patients and a vehicle to kill cancer cells. Oncotarget 8:82803–82823. Scholar
  44. Ma S, Jia R, Li D, Shen B (2015) Targeting cellular metabolism chemosensitizes the doxorubicin-resistant human breast adenocarcinoma cells. Biomed Res Int 2015:1–8. Scholar
  45. Maley CC, Aktipis A, Graham TA, Sottoriva A, Boddy AM, Janiszewska M et al (2017) Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer 17:605–619. Scholar
  46. Merlo LMF, Pepper JW, Reid BJ, Maley CC (2006) Cancer as an evolutionary and ecological process. Nat Rev Cancer 6:924–935. Scholar
  47. Morandi A, Indraccolo S (2017) Linking metabolic reprogramming to therapy resistance in cancer. Biochimica et Biophysica Acta – Rev Cancer 1868:1–6. Scholar
  48. Nguyen TL, Durán RV (2018) Glutamine metabolism in cancer therapy. Cancer Drug Resist 1:126–138. Scholar
  49. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28. Scholar
  50. Pastò A, Pagotto A, Pilotto G, De Paoli A, De Salvo GL, Baldoni A et al (2017) Resistance to glucose starvation as metabolic trait of platinum- resistant human epithelial ovarian cancer cells. Oncotarget 8:6433–6445. Scholar
  51. Polyak K (2007) Breast cancer stem cells: a case of mistaken identity? Stem Cell Rev 3:107–109. Scholar
  52. Qian W, Nishikawa M, Haque AM, Hirose M, Mashimo M, Sato E, Inoue M (2005) Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death. Am J Phys Cell Phys 289:C1466–C1475. Scholar
  53. Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180. Scholar
  54. Rodríguez-Enríquez S, Torres-Márquez ME, Moreno-Sánchez R (2000) Substrate oxidation and ATP supply in AS-30D hepatoma cells. Arch Biochem Biophys 375:21–30. Scholar
  55. Rodríguez-Enríquez S, Vital-González PA, Flores-Rodríguez FL, Marín-Hernández A, Ruiz-Azuara L, Moreno-Sánchez R (2006) Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. Toxicol Appl Pharmacol 215:208–217. Scholar
  56. Roh JL, Jang H, Kim EH, Shin D (2017) Targeting of the glutathione, thioredoxin, and Nrf2 antioxidant systems in head and neck cancer. Antioxid Redox Signal 27:106–114. Scholar
  57. Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG et al (2016) Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov 6:147–153. Scholar
  58. Salgia R, Kulkarni P (2018) The genetic/non-genetic duality of drug “resistance” in cancer. Trends Cancer 4:110–118. Scholar
  59. Sancho P, Burgos-Ramos E, Tavera A, Bou Kheir T, Jagust P, Schoenhals M et al (2015) MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab 22:590–605. Scholar
  60. Semenza GL (2012) Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci 33:207–214. Scholar
  61. Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A et al (2016) Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F. N Engl J Med 374:54–61. Scholar
  62. Silva AS, Kam Y, Khin ZP, Minton SE, Gillies RJ, Gatenby RA (2012) Evolutionary approaches to prolong progression-free survival in breast cancer. Cancer Res 72:6362–6370. Scholar
  63. Son B, Lee S, Youn H, Kim E, Kim W, Youn B (2017) The role of tumor microenvironment in therapeutic resistance. Oncotarget 8:3933–3945. Scholar
  64. Sun D, Dalin S, Hemann MT, Lauffenburger DA, Zhao B (2016) Differential selective pressure alters rate of drug resistance acquisition in heterogeneous tumor populations. Sci Rep 6:1–13. Scholar
  65. Swanton C (2013) Intratumour heterogeneity : evolution through space and time an evolutionary perspective on cancer heterogeneity. Cancer Res 72:4875–4882. IntratumourCrossRefGoogle Scholar
  66. van Niekerk G, Nell T, Engelbrecht AM (2017) Domesticating cancer: an evolutionary strategy in the war on Cancer. Front Oncol 7:1–8. Scholar
  67. Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239. Scholar
  68. Viale A, Corti D, Draetta GF (2015) Tumors and mitochondrial respiration: a neglected connection. Cancer Res 75:1–5. Scholar
  69. Warburg O (1956) On the origin of cancer cells on the origin of cancer. Science 123:309–314. Scholar
  70. Xue Y, Martelotto L, Baslan T, Vides A, Solomon M, Mai TT et al (2017) An approach to suppress the evolution of resistance in BRAF V600E-mutant cancer. Nat Med 23:929–937. Scholar
  71. Ye J, Zou M, Li P, Liu H (2018) MicroRNA regulation of energy metabolism to induce chemoresistance in cancers. Technol Cancer Res Treat 17:1–6. Scholar
  72. Yu L, Lu M, Jia D, Ma J, Ben-Jacob E, Levine H et al (2017) Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res 77:1564–1574. Scholar
  73. Zhang L, Yang H, Zhang W, Liang Z, Huang Q, Guoqiang X et al (2017a) Clk1–regulated aerobic glycolysis is involved in gliomas chemoresistance. J Neurochem 142:574–588. Scholar
  74. Zhang J, Cunningham JJ, Brown JS, Gatenby RA (2017b) Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer. Nat Commun 8:1–9.
  75. Zhao JG, Ren KM, Tang J (2014) Overcoming 5-Fu resistance in human non-small cell lung cancer cells by the combination of 5-Fu and cisplatin through the inhibition of glucose metabolism. Tumor Biol 35:12305–12315.
  76. Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J et al (2012) Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res 72:304–314. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Sofia C. Nunes
    • 1
    • 2
  1. 1.CEDOC, Chronic Diseases Research Centre, NOVA Medical School | Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal
  2. 2.Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG)LisbonPortugal

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