Therapeutic potential of mTOR inhibitors for targeting cancer stem cells

British Journal of Clinical Pharmacology

Volumn , Issue , 2016, Pages 1180-1188

  Francipane, Maria Giovanna ^a,b   Lagasse, Eric ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b RiMED Foundation   (Italy)

Author keywords

cancer stem cells, drug resistance; mTOR; personalized medicine; tumour heterogeneity

Indexed keywords

2 (4 AMINO 1 ISOPROPYL 1H PYRAZOLO[3,4 D]PYRIMIDIN 3 YL) 1H INDOL 5 OL; 5 [2 (2,6 DIMETHYLMORPHOLINO) 4 MORPHOLINOPYRIDO[2,3 D]PYRIMIDIN 7 YL] 2 METHOXYBENZENEMETHANOL; AZD 8055; DACTOLISIB; ERLOTINIB; FC 85; ISA 27; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; RAPAMYCIN; RAPAMYCIN DERIVATIVE; TAMOXIFEN; TORIN 1; UNCLASSIFIED DRUG; WYE 354;

ANTINEOPLASTIC ACTIVITY; BREAST CANCER; CANCER RESISTANCE; CANCER STEM CELL; COLON CANCER; DRUG EFFICACY; GLIOBLASTOMA; HUMAN; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PERSONALIZED MEDICINE; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; SIGNAL TRANSDUCTION; STEM CELL;

EID: 84999587151     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12844     Document Type: Review

References (81)

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5–29.
2. Wong KM, Hudson TJ, McPherson JD. Unraveling the genetics of cancer: genome sequencing and beyond. Annu Rev Genomics Hum Genet 2011; 12: 407–30.
3. Akhavan D, Cloughesy TF, Mischel PS. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro Oncol 2010; 12: 882–9.
4. Hynes NE, Boulay A. The mTOR pathway in breast cancer. J Mammary Gland Biol Neoplasia 2006; 11: 53–61.
5. Matsubara S, Ding Q, Miyazaki Y, Kuwahata T, Tsukasa K, Takao S. mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci Rep 2013; 3: 3230.
6. Francipane MG, Lagasse E. mTOR pathway in colorectal cancer: an update. Oncotarget 2014; 5: 49–66.
7. Morgan TM, Koreckij TD, Corey E. Targeted therapy for advanced prostate cancer: inhibition of the PI3K/Akt/mTOR pathway. Curr Cancer Drug Targets 2009; 9: 237–49.
8. Dobbin ZC, Landen CN. The importance of the PI3K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 2013; 14: 8213–27.
9. Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I, Shackleford GM, Cavenee WK, Mellinghoff IK, Cloughesy TF, Sawyers CL, Mischel PS. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 2006; 66: 7864–9.
10. Huang Z, Wu Y, Zhou X, Qian J, Zhu W, Shu Y, Liu P. Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. Future Oncol 2015; 11: 1687–99.
11. Buermans HP, den Dunnen JT. Next generation sequencing technology: Advances and applications. Biochim Biophys Acta 2014; 1842: 1932–41.
12. Hoelder S, Clarke PA, Workman P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol Oncol 2012; 6: 155–76.
13. Vacchelli E, Eggermont A, Galon J, Sautes-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: Monoclonal antibodies in cancer therapy. Oncoimmunology 2013; 2: e22789.
14. Widakowich C, de Castro G Jr, de Azambuja E, Dinh P, Awada A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist 2007; 12: 1443–55.
15. Lippert TH, Ruoff HJ, Volm M. Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure. Arzneimittelforschung 2008; 58: 261–4.
16. Francipane M, Lagasse E. A Study of Cancer Heterogeneity: From Genetic Instability to Epigenetic Diversity in Colorectal Cancer. In: Cancer Targeted Drug Delivery, eds Bae YH, Mrsny RJ, Park K. New York: Springer, 2013; 363–88.
17. Fedele C, Tothill RW, McArthur GA. Navigating the challenge of tumor heterogeneity in cancer therapy. Cancer discovery 2014; 4: 146–8.
18. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 2012; 21: 283–96.
19. Nowell PC. The clonal evolution of tumor cell populations. Science 1976; 194: 23–8.
20. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011; 11: 726–34.
21. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet 2009; 25: 30–8.
22. Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 2011; 17: 320–9.
23. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–8.
24. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–7.
25. Odoux C, Fohrer H, Hoppo T, Guzik L, Stolz DB, Lewis DW, Gollin SM, Gamblin TC, Geller DA, Lagasse E. A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res 2008; 68: 6932–41.
26. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 2011; 146: 633–44.
27. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 2011; 108: 7950–5.
28. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011; 108: 1397–402.
29. Lagasse E. Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer. Gene Ther 2008; 15: 136–42.
30. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell 2014; 14: 275–91.
31. Kirk R. Genetics: Personalized medicine and tumour heterogeneity. Nat Rev Clin Oncol 2012; 9: 250.
32. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–92.
33. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K, Yamanaka S. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24: 6710–8.
34. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2: 489–501.
35. Maehama T, Dixon JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 1999; 9: 125–8.
36. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4: 648–57.
37. Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol 2004; 24: 7965–75.
38. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol : CB 2005; 15: 702–13.
39. Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, Hara K, Kemp BE, Witters LA, Mimura O, Yonezawa K. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 2003; 8: 65–79.
40. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007; 8: 774–85.
41. Yuan HX, Xiong Y, Guan KL. Nutrient sensing, metabolism, and cell growth control. Mol Cell 2013; 49: 379–87.
42. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006; 126: 955–68.
43. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30: 214–26.
44. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 2002; 16: 1472–87.
45. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009; 20: 1981–91.
46. Ben-Sahra I, Howell JJ, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 2013; 339: 1323–8.
47. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011; 144: 757–68.
48. Liu P, Gan W, Chin YR, Ogura K, Guo J, Zhang J, Wang B, Blenis J, Cantley LC, Toker A, Su B, Wei W. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discovery 2015; 5: 1194–209.
49. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–101.
50. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122–8.
51. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296–302.
52. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008; 416: 375–85.
53. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27: 5497–510.
54. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discovery 2014; 4: 554–63.
55. Iglesias-Bartolome R, Gutkind SJ. Exploiting the mTOR paradox for disease prevention. Oncotarget 2012; 3: 1061–3.
56. Kharas MG, Okabe R, Ganis JJ, Gozo M, Khandan T, Paktinat M, Gilliland DG, Gritsman K. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 2010; 115: 1406–15.
57. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, Haug JS, Rupp D, Porter-Westpfahl KS, Wiedemann LM, Wu H, Li L. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441: 518–22.
58. Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–82.
59. Chen C, Liu Y, Liu R, Ikenoue T, Guan KL, Liu Y, Zheng P. TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 2008; 205: 2397–408.
60. Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009; 2: ra75.
61. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell 2009; 5: 279–89.
62. Yilmaz OH, Katajisto P, Lamming DW, Gultekin Y, Bauer-Rowe KE, Sengupta S, Birsoy K, Dursun A, Yilmaz VO, Selig M, Nielsen GP, Mino-Kenudson M, Zukerberg LR, Bhan AK, Deshpande V, Sabatini DM. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 2012; 486: 490–5.
63. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460: 392–5.
64. Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007; 109: 3509–12.
65. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167: 399–403.
66. Rozengurt E, Soares HP, Sinnet-Smith J. Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance. Mol Cancer Ther 2014; 13: 2477–88.
67. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 2013; 10: 143–53.
68. Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther 2011; 10: 395–403.
69. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7: e38.
70. Kolev VN, Wright QG, Vidal CM, Ring JE, Shapiro IM, Ricono J, Weaver DT, Padval MV, Pachter JA, Xu Q. PI3K/mTOR dual inhibitor VS-5584 preferentially targets cancer stem cells. Cancer Res 2015; 75: 446–55.
71. Daniele S, Taliani S, da Pozzo E, Giacomelli C, Costa B, Trincavelli ML, Rossi L, la Pietra V, Barresi E, Carotenuto A, Limatola A, Lamberti A, Marinelli L, Novellino E, da Settimo F, Martini C. Apoptosis therapy in cancer: the first single-molecule co-activating p53 and the translocator protein in glioblastoma. Sci Rep 2014; 4: 4749.
72. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, Margolick JB, Liotta LA, Petricoin E, 3rd, Zhang Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 2007; 104: 16158–63.
73. Karthik GM, Ma R, Lovrot J, Kis LL, Lindh C, Blomquist L, Fredriksson I, Bergh J, Hartman J. mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells. Cancer Lett 2015; 367: 76–87.
74. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–8.
75. Wei F, Zhang Y, Geng L, Zhang P, Wang G, Liu Y. mTOR inhibition induces EGFR feedback activation in association with its resistance to human pancreatic cancer. Int J Mol Sci 2015; 16: 3267–82.
76. Francipane MG, Lagasse E. Selective targeting of human colon cancer stem-like cells by the mTOR inhibitor Torin-1. Oncotarget 2013; 4: 1948–62.
77. Komori J, Boone L, DeWard A, Hoppo T, Lagasse E. The mouse lymph node as an ectopic transplantation site for multiple tissues. Nat Biotechnol 2012; 30: 976–83.
78. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 2009; 106: 268–73.
79. Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ, Kearsley JH, Li Y. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis 2013; 4: e875.
80. Alvero AB, Montagna MK, Holmberg JC, Craveiro V, Brown D, Mor G. Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells. Mol Cancer Ther 2011; 10: 1385–93.
81. Francipane MG, Chandler J, Lagasse E. Cancer stem cells: a moving target. Curr Pathobiology Rep 2013; 1: 111–8.