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Oxidative Medicine and Cellular Longevity
Volume 2017 (2017), Article ID 1726078, 10 pages
https://doi.org/10.1155/2017/1726078
Review Article

Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity

Department of Visceral Surgery, Lausanne University Hospital, Pavillon 4, Av. de Beaumont, 1011 Lausanne, Switzerland

Correspondence should be addressed to Olivier Dormond; hc.vuhc@dnomrod.reivilo

Received 4 November 2016; Accepted 22 January 2017; Published 9 February 2017

Academic Editor: Zhiyou Cai

Copyright © 2017 Seraina Faes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. I. B. Weinstein and A. Joe, “Oncogene addiction,” Cancer Research, vol. 68, no. 9, pp. 3077–3080, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. B. J. Druker, M. Talpaz, D. J. Resta et al., “Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia,” New England Journal of Medicine, vol. 344, no. 14, pp. 1031–1037, 2001. View at Publisher · View at Google Scholar · View at Scopus
  3. D. R. Welch, “Tumor heterogeneity—a “contemporary concept” founded on historical insights and predictions,” Cancer Research, vol. 76, no. 1, pp. 4–6, 2016. View at Publisher · View at Google Scholar · View at Scopus
  4. M. C. Lloyd, J. J. Cunningham, M. M. Bui, R. J. Gillies, J. S. Brown, and R. A. Gatenby, “Darwinian dynamics of intratumoral heterogeneity: not solely random mutations but also variable environmental selection forces,” Cancer Research, vol. 76, no. 11, pp. 3136–3144, 2016. View at Publisher · View at Google Scholar · View at Scopus
  5. L. A. Garraway and P. A. Jänne, “Circumventing cancer drug resistance in the era of personalized medicine,” Cancer Discovery, vol. 2, no. 3, pp. 214–226, 2012. View at Publisher · View at Google Scholar · View at Scopus
  6. B. K. Kennedy and D. W. Lamming, “The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging,” Cell Metabolism, vol. 23, no. 6, pp. 990–1003, 2016. View at Publisher · View at Google Scholar · View at Scopus
  7. Y. C. Kim and K.-L. Guan, “MTOR: a pharmacologic target for autophagy regulation,” The Journal of Clinical Investigation, vol. 125, no. 1, pp. 25–32, 2015. View at Publisher · View at Google Scholar · View at Scopus
  8. A. M. Arsham, J. J. Howell, and M. C. Simon, “A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets,” Journal of Biological Chemistry, vol. 278, no. 32, pp. 29655–29660, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. A. D. Balgi, G. H. Diering, E. Donohue et al., “Regulation of mTORC1 signaling by pH,” PLoS ONE, vol. 6, no. 6, Article ID e21549, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. K. Inoki, Y. Li, T. Zhu, J. Wu, and K.-L. Guan, “TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling,” Nature Cell Biology, vol. 4, no. 9, pp. 648–657, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. B. D. Manning, A. R. Tee, M. N. Logsdon, J. Blenis, and L. C. Cantley, “Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway,” Molecular Cell, vol. 10, no. 1, pp. 151–162, 2002. View at Publisher · View at Google Scholar · View at Scopus
  12. L. Ma, Z. Chen, H. Erdjument-Bromage, P. Tempst, and P. P. Pandolfi, “Phosphorylation and functional inactivation of TSC2 by Erk: implications for tuberous sclerosis and cancer pathogenesis,” Cell, vol. 121, no. 2, pp. 179–193, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. P. B. Crino, K. L. Nathanson, and E. P. Henske, “The tuberous sclerosis complex,” The New England Journal of Medicine, vol. 355, no. 13, pp. 1345–1356, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Laplante and D. M. Sabatini, “Regulation of mTORC1 and its impact on gene expression at a glance,” Journal of Cell Science, vol. 126, no. 8, pp. 1713–1719, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. M. Shimobayashi and M. N. Hall, “Making new contacts: the mTOR network in metabolism and signalling crosstalk,” Nature Reviews Molecular Cell Biology, vol. 15, no. 3, pp. 155–162, 2014. View at Publisher · View at Google Scholar · View at Scopus
  16. J. A. McCubrey, L. S. Steelman, W. H. Chappell et al., “Mutations and deregulation of Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mtor cascades which alter therapy response,” Oncotarget, vol. 3, no. 9, pp. 954–987, 2012. View at Publisher · View at Google Scholar · View at Scopus
  17. N. Wagle, B. C. Grabiner, E. M. Van Allen et al., “Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib,” Cancer Discovery, vol. 4, no. 5, pp. 546–553, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. B. C. Grabiner, V. Nardi, K. Birsoy et al., “A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity,” Cancer Discovery, vol. 4, no. 5, pp. 554–563, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. K. Inoki, M. N. Corradetti, and K.-L. Guan, “Dysregulation of the TSC-mTOR pathway in human disease,” Nature Genetics, vol. 37, no. 1, pp. 19–24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. W. J. Oh and E. Jacinto, “mTOR complex 2 signaling and functions,” Cell Cycle, vol. 10, no. 14, pp. 2305–2316, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. L. C. Kim, R. S. Cook, and J. Chen, “mTORC1 and mTORC2 in cancer and the tumor microenvironment,” Oncogene, 2016. View at Publisher · View at Google Scholar
  22. K. Tanaka, I. Babic, D. Nathanson et al., “Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance,” Cancer Discovery, vol. 1, no. 6, pp. 524–538, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. D. A. Guertin, D. M. Stevens, M. Saitoh et al., “mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice,” Cancer Cell, vol. 15, no. 2, pp. 148–159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. D. R. Driscoll, S. A. Karim, M. Sano et al., “mTORC2 signaling drives the development and progression of pancreatic cancer,” Cancer Research, vol. 76, no. 23, pp. 6911–6923, 2016. View at Publisher · View at Google Scholar
  25. D. Roulin, Y. Cerantola, A. Dormond-Meuwly, N. Demartines, and O. Dormond, “Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo,” Molecular Cancer, vol. 9, article 57, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Xie, X. Wang, and C. G. Proud, “mTOR inhibitors in cancer therapy,” F1000Research, vol. 5, article 2078, 2016. View at Publisher · View at Google Scholar
  27. C. H. S. Aylett, E. Sauer, S. Imseng et al., “Architecture of human mTOR complex 1,” Science, vol. 351, no. 6268, pp. 48–52, 2016. View at Publisher · View at Google Scholar · View at Scopus
  28. H.-X. Yuan and K.-L. Guan, “Structural insights of mTOR complex 1,” Cell Research, vol. 26, no. 3, pp. 267–268, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. C. C. Thoreen, S. A. Kang, J. W. Chang et al., “An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1,” Journal of Biological Chemistry, vol. 284, no. 12, pp. 8023–8032, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. D. Benjamin, M. Colombi, C. Moroni, and M. N. Hall, “Rapamycin passes the torch: a new generation of mTOR inhibitors,” Nature Reviews Drug Discovery, vol. 10, no. 11, pp. 868–880, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. S. A. Wander, B. T. Hennessy, and J. M. Slingerland, “Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy,” Journal of Clinical Investigation, vol. 121, no. 4, pp. 1231–1241, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. V. S. Rodrik-Outmezguine, M. Okaniwa, Z. Yao et al., “Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor,” Nature, vol. 534, no. 7606, pp. 272–276, 2016. View at Publisher · View at Google Scholar · View at Scopus
  33. A. W. Thomson, H. R. Turnquist, and G. Raimondi, “Immunoregulatory functions of mTOR inhibition,” Nature Reviews Immunology, vol. 9, no. 5, pp. 324–337, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Waldner, D. Fantus, M. Solari, and A. W. Thomson, “New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation,” British Journal of Clinical Pharmacology, vol. 82, no. 5, pp. 1158–1170, 2016. View at Publisher · View at Google Scholar · View at Scopus
  35. S. L. Habib, N. Y. Al-Obaidi, M. Nowacki et al., “Is mTOR inhibitor good enough for treatment all tumors in TSC patients?” Journal of Cancer, vol. 7, no. 12, pp. 1621–1631, 2016. View at Publisher · View at Google Scholar
  36. T. H. Sasongko, N. F. Ismail, and Z. Zabidi-Hussin, “Rapamycin and rapalogs for tuberous sclerosis complex,” The Cochrane Database of Systematic Reviews, vol. 7, Article ID CD011272, 2016. View at Google Scholar
  37. D. A. Krueger, M. M. Care, K. Holland et al., “Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis,” New England Journal of Medicine, vol. 363, no. 19, pp. 1801–1811, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. F. Chiarini, C. Evangelisti, J. A. McCubrey, and A. M. Martelli, “Current treatment strategies for inhibiting mTOR in cancer,” Trends in Pharmacological Sciences, vol. 36, no. 2, pp. 124–135, 2015. View at Publisher · View at Google Scholar · View at Scopus
  39. G. Hudes, M. Carducci, P. Tomczak et al., “Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma,” The New England Journal of Medicine, vol. 356, no. 22, pp. 2271–2281, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. R. J. Motzer, B. Escudier, S. Oudard et al., “Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial,” The Lancet, vol. 372, no. 9637, pp. 449–456, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. J. C. Yao, M. H. Shah, T. Ito et al., “Everolimus for advanced pancreatic neuroendocrine tumors,” New England Journal of Medicine, vol. 364, no. 6, pp. 514–523, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. J. Baselga, M. Campone, M. Piccart et al., “Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer,” New England Journal of Medicine, vol. 366, no. 6, pp. 520–529, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. J. C. Yao, N. Fazio, S. Singh et al., “Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study,” The Lancet, vol. 387, no. 10022, pp. 968–977, 2016. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Hess, R. Herbrecht, J. Romaguera et al., “Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma,” Journal of Clinical Oncology, vol. 27, no. 23, pp. 3822–3829, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. N. Pallet and C. Legendre, “Adverse events associated with mTOR inhibitors,” Expert Opinion on Drug Safety, vol. 12, no. 2, pp. 177–186, 2013. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Sadowski, K. Kotulska, and S. Jóźwiak, “Management of side effects of mTOR inhibitors in tuberous sclerosis patients,” Pharmacological Reports, vol. 68, no. 3, pp. 536–542, 2016. View at Publisher · View at Google Scholar · View at Scopus
  47. J. Li, S. G. Kim, and J. Blenis, “Rapamycin: one drug, many effects,” Cell Metabolism, vol. 19, no. 3, pp. 373–379, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. C. C. Thoreen and D. M. Sabatini, “Rapamycin inhibits mTORC1, but not completely,” Autophagy, vol. 5, no. 5, pp. 725–726, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. B. Blaser, L. Waselle, A. Dormond-Meuwly et al., “Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells,” BMC Cancer, vol. 12, article 86, 2012. View at Publisher · View at Google Scholar · View at Scopus
  50. D. C. Cho, M. B. Cohen, D. J. Panka et al., “The efficacy of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal cell carcinoma,” Clinical Cancer Research, vol. 16, no. 14, pp. 3628–3638, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. P. M. LoRusso, “Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors,” Journal of Clinical Oncology, vol. 34, no. 31, pp. 3803–3815, 2016. View at Publisher · View at Google Scholar
  52. M. E. Gorre, M. Mohammed, K. Ellwood et al., “Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification,” Science, vol. 293, no. 5531, pp. 876–880, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Kobayashi, T. J. Boggon, T. Dayaram et al., “EGFR mutation and resistance of non-small-cell lung cancer to gefitinib,” The New England Journal of Medicine, vol. 352, no. 8, pp. 786–792, 2005. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. L. Choi, M. Soda, Y. Yamashita et al., “EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors,” The New England Journal of Medicine, vol. 363, no. 18, pp. 1734–1739, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. E. J. Brown, P. A. Beal, C. T. Keith, J. Chen, T. B. Shin, and S. L. Schreiber, “Control of p70 S6 kinase by kinase activity of FRAP in vivo,” Nature, vol. 377, no. 6548, pp. 441–446, 1995. View at Publisher · View at Google Scholar · View at Scopus
  56. M. C. Lorenz and J. Heitman, “TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin,” Journal of Biological Chemistry, vol. 270, no. 46, pp. 27531–27537, 1995. View at Publisher · View at Google Scholar · View at Scopus
  57. N. Wagle, B. C. Grabiner, E. M. Van Allen et al., “Response and acquired resistance to everolimus in anaplastic thyroid cancer,” The New England Journal of Medicine, vol. 371, no. 15, pp. 1426–1433, 2014. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Efeyan and D. M. Sabatini, “MTOR and cancer: many loops in one pathway,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 169–176, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Ilagan and B. D. Manning, “Emerging role of mTOR in the response to cancer therapeutics,” Trends in Cancer, vol. 2, no. 5, pp. 241–251, 2016. View at Publisher · View at Google Scholar · View at Scopus
  60. H. Zhang, G. Cicchetti, H. Onda et al., “Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR,” Journal of Clinical Investigation, vol. 112, no. 8, pp. 1223–1233, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. L. S. Harrington, G. M. Findlay, A. Gray et al., “The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins,” Journal of Cell Biology, vol. 166, no. 2, pp. 213–223, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. T. Haruta, T. Uno, J. Kawahara et al., “A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1,” Molecular Endocrinology, vol. 14, no. 6, pp. 783–794, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. P. P. Hsu, S. A. Kang, J. Rameseder et al., “The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling,” Science, vol. 332, no. 6035, pp. 1317–1322, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. Y. Yu, S.-O. Yoon, G. Poulogiannis et al., “Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling,” Science, vol. 332, no. 6035, pp. 1322–1326, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. P. Liu, W. Gan, H. Inuzuka et al., “Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis,” Nature Cell Biology, vol. 15, no. 11, pp. 1340–1350, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Xie and C. G. Proud, “Crosstalk between mTor complexes,” Nature Cell Biology, vol. 15, no. 11, pp. 1263–1265, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. L.-A. Julien, A. Carriere, J. Moreau, and P. P. Roux, “mTORC1-activated S6K1 phosphorylates rictor on threonine 1135 and regulates mTORC2 signaling,” Molecular and Cellular Biology, vol. 30, no. 4, pp. 908–921, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. C. C. Dibble, J. M. Asara, and B. D. Manning, “Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1,” Molecular and Cellular Biology, vol. 29, no. 21, pp. 5657–5670, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. E. Rozengurt, H. P. Soares, and J. Sinnet-Smith, “Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance,” Molecular Cancer Therapeutics, vol. 13, no. 11, pp. 2477–2488, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Dufour, A. Dormond-Meuwly, N. Demartines, and O. Dormond, “Targeting the mammalian target of rapamycin (mTOR) in cancer therapy: lessons from past and future perspectives,” Cancers, vol. 3, no. 2, pp. 2478–2500, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. K. E. O'Reilly, F. Rojo, Q.-B. She et al., “mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt,” Cancer Research, vol. 66, no. 3, pp. 1500–1508, 2006. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Tabernero, F. Rojo, E. Calvo et al., “Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 26, no. 10, pp. 1603–1610, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. T. F. Cloughesy, K. Yoshimoto, P. Nghiemphu et al., “Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma,” PLOS Medicine, vol. 5, no. 1, article e8, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. A. Carracedo, L. Ma, J. Teruya-Feldstein et al., “Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer,” Journal of Clinical Investigation, vol. 118, no. 9, pp. 3065–3074, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. V. S. Rodrik-Outmezguine, S. Chandarlapaty, N. C. Pagano et al., “mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling,” Cancer Discovery, vol. 1, no. 3, pp. 248–259, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. M. Dufour, A. Dormond-Meuwly, C. Pythoud, N. Demartines, and O. Dormond, “Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects,” Biochemical and Biophysical Research Communications, vol. 438, no. 1, pp. 32–37, 2013. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Faes and O. Dormond, “PI3K and AKT: unfaithful partners in cancer,” International Journal of Molecular Sciences, vol. 16, no. 9, pp. 21138–21152, 2015. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Hoang, A. Benavides, Y. Shi et al., “The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/ eukaryotic translation initiation factor 4E (eIF-4E)/ RAF pathway and activation is a mechanism of resistance,” Journal of Biological Chemistry, vol. 287, no. 26, pp. 21796–21805, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. H. P. Soares, Y. Ni, K. Kisfalvi, J. Sinnett-Smith, and E. Rozengurt, “Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells,” PLoS ONE, vol. 8, no. 2, Article ID e57289, 2013. View at Publisher · View at Google Scholar · View at Scopus
  80. N. McGranahan and C. Swanton, “Biological and therapeutic impact of intratumor heterogeneity in cancer evolution,” Cancer Cell, vol. 27, no. 1, pp. 15–26, 2015. View at Publisher · View at Google Scholar · View at Scopus
  81. G. H. Heppner, “Tumor heterogeneity,” Cancer Research, vol. 44, no. 6, pp. 2259–2265, 1984. View at Google Scholar · View at Scopus
  82. A. P. Patel, I. Tirosh, J. J. Trombetta et al., “Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma,” Science, vol. 344, no. 6190, pp. 1396–1401, 2014. View at Publisher · View at Google Scholar · View at Scopus
  83. J. Zhang, J. Fujimoto, J. Zhang et al., “Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing,” Science, vol. 346, no. 6206, pp. 256–259, 2014. View at Publisher · View at Google Scholar · View at Scopus
  84. G. Armengol, F. Rojo, J. Castellví et al., “4E-binding protein 1: a key molecular ‘funnel factor’ in human cancer with clinical implications,” Cancer Research, vol. 67, no. 16, pp. 7551–7555, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. F. Rojo, L. Najera, J. Lirola et al., “4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis,” Clinical Cancer Research, vol. 13, no. 1, pp. 81–89, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. M. Gerlinger, A. J. Rowan, S. Horswell et al., “Intratumor heterogeneity and branched evolution revealed by multiregion sequencing,” New England Journal of Medicine, vol. 366, no. 10, pp. 883–892, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Akcakanat, A. Sahin, A. N. Shaye, M. A. Velasco, and F. Meric-Bernstam, “Comparison of Akt/mTOR signaling in primary breast tumors and matched distant metastases,” Cancer, vol. 112, no. 11, pp. 2352–2358, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. T. Sato, A. Nakashima, L. Guo, K. Coffman, and F. Tamanoi, “Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer,” Oncogene, vol. 29, no. 18, pp. 2746–2752, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Xu, C. G. Pham, S. K. Albanese et al., “Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin,” Journal of Clinical Investigation, vol. 126, no. 9, pp. 3526–3540, 2016. View at Publisher · View at Google Scholar
  90. J. Dupont Jensen, A.-V. Laenkholm, A. Knoop et al., “PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer,” Clinical Cancer Research, vol. 17, no. 4, pp. 667–677, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. S. D. Richman, P. Chambers, M. T. Seymour et al., “Intra-tumoral heterogeneity of KRAS and BRAF mutation status in patients with advanced colorectal cancer (aCRC) and cost-effectiveness of multiple sample testing,” Analytical Cellular Pathology, vol. 34, no. 1-2, pp. 61–66, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. L. Losi, B. Baisse, H. Bouzourene, and J. Benhattar, “Evolution of intratumoral genetic heterogeneity during colorectal cancer progression,” Carcinogenesis, vol. 26, no. 5, pp. 916–922, 2005. View at Publisher · View at Google Scholar · View at Scopus
  93. M. J. Gerdes, C. J. Sevinsky, A. Sood et al., “Highly multiplexed single-cell analysis of formalinfixed, paraffin-embedded cancer tissue,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 29, pp. 11982–11987, 2013. View at Publisher · View at Google Scholar · View at Scopus
  94. M. J. Gerdes, A. Sood, C. Sevinsky, A. D. Pris, M. I. Zavodszky, and F. Ginty, “Emerging understanding of multiscale tumor heterogeneity,” Frontiers in Oncology, vol. 4, article no. 366, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. W. R. Wilson and M. P. Hay, “Targeting hypoxia in cancer therapy,” Nature Reviews Cancer, vol. 11, no. 6, pp. 393–410, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. S. Faes, A. Planche, E. Uldry et al., “Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors,” Oncotarget, vol. 7, no. 24, pp. 36666–36680, 2016. View at Publisher · View at Google Scholar · View at Scopus
  97. K. X. Knaup, K. Jozefowski, R. Schmidt et al., “Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability,” Molecular Cancer Research, vol. 7, no. 1, pp. 88–98, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. A. Schneider, R. H. Younis, and J. S. Gutkind, “Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma,” Neoplasia, vol. 10, no. 11, pp. 1295–1302, 2008. View at Publisher · View at Google Scholar · View at Scopus
  99. W. H. Dragowska, M. Verreault, D. T. T. Yapp et al., “Decreased levels of hypoxic cells in gefitinib treated ER+ HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway: therapeutic implications for combination therapy with rapamycin,” Breast Cancer Research and Treatment, vol. 106, no. 3, pp. 319–331, 2007. View at Publisher · View at Google Scholar · View at Scopus
  100. E. Allen, P. Miéville, C. M. Warren et al., “Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR signaling,” Cell Reports, vol. 15, no. 6, pp. 1144–1160, 2016. View at Publisher · View at Google Scholar · View at Scopus
  101. G. Jiménez-Valerio, M. Martínez-Lozano, N. Bassani et al., “Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients,” Cell Reports, vol. 15, no. 6, pp. 1134–1143, 2016. View at Publisher · View at Google Scholar · View at Scopus
  102. W. Palm, Y. Park, K. Wright, N. N. Pavlova, D. A. Tuveson, and C. B. Thompson, “The utilization of extracellular proteins as nutrients is suppressed by mTORC1,” Cell, vol. 162, no. 2, pp. 259–270, 2015. View at Publisher · View at Google Scholar · View at Scopus
  103. J. Pastorek and S. Pastorekova, “Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use,” Seminars in Cancer Biology, vol. 31, pp. 52–64, 2015. View at Publisher · View at Google Scholar · View at Scopus
  104. H. Cam, J. B. Easton, A. High, and P. J. Houghton, “mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α,” Molecular Cell, vol. 40, no. 4, pp. 509–520, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. J. Brugarolas, K. Lei, R. L. Hurley et al., “Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex,” Genes and Development, vol. 18, no. 23, pp. 2893–2904, 2004. View at Publisher · View at Google Scholar · View at Scopus
  106. B. G. Wouters and M. Koritzinsky, “Hypoxia signalling through mTOR and the unfolded protein response in cancer,” Nature Reviews Cancer, vol. 8, no. 11, pp. 851–864, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. R. A. Gatenby and R. J. Gillies, “Why do cancers have high aerobic glycolysis?” Nature Reviews Cancer, vol. 4, no. 11, pp. 891–899, 2004. View at Publisher · View at Google Scholar · View at Scopus
  108. Y. Kato, S. Ozawa, C. Miyamoto et al., “Acidic extracellular microenvironment and cancer,” Cancer Cell International, vol. 13, no. 1, article 89, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. B. D. Fonseca, G. H. Diering, M. A. Bidinosti et al., “Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling,” Journal of Biological Chemistry, vol. 287, no. 21, pp. 17530–17545, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. S. Faes, A. P. Duval, A. Planche et al., “Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors,” Molecular Cancer, vol. 15, no. 1, article no. 78, 2016. View at Google Scholar