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Open Library of Bioscience

The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines.

Abstract

Keywords

References

1. Thorpe LM, Yuzugullu H, Zhao JJ (2015) PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 15(1):7–24 [PMID: 4384662]
2. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22
3. Menon S, Manning BD (2008) Common corruption of the mTOR signaling network in human tumors. Oncogene 27(2):S43–S51 [PMID: 3752670]
4. Zaytseva YY et al (2012) mTOR inhibitors in cancer therapy. Cancer Lett 319(1):1–7
5. Pedroza DA et al (2020) Progesterone receptor membrane component 1 promotes the growth of breast cancers by altering the phosphoproteome and augmenting EGFR/PI3K/AKT signalling. Br J Cancer 123:1326–1335 [PMID: 7553958]
6. Markova B et al (2010) Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway. Oncogene 29(5):739–751
7. Cornu M, Albert V, Hall MN (2013) mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 23(1):53–62
8. Zhou H, Luo Y, Huang S (2010) Updates of mTOR inhibitors. Anti-Cancer Agents Med Chem 10(7):571–581
9. Francipane MG, Lagasse E (2014) mTOR pathway in colorectal cancer: an update. Oncotarget 5(1):49
10. Bellizzi AM et al (2010) The mTOR pathway is frequently activated in pancreatic ductal adenocarcinoma and chronic pancreatitis. Appl Immunohistochem Mol Morphol 18(5):442–447
11. Li X et al (2016) PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7(22):33440 [PMID: 5078108]
12. Hütt-Cabezas M et al (2013) Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target. Neurooncology 15(12):1604–1614
13. Bilanges B, Posor Y, Vanhaesebroeck B (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20(9):515–534
14. Lee Y-R, Chen M, Pandolfi PP (2018) The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 19(9):547–562
15. Hoxhaj G, Manning BD (2020) The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 20(2):74–88
16. Valvezan AJ, Manning BD (2019) Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab 1(3):321–333
17. Chen X et al (2018) Cryo-EM structure of human mTOR complex 2. Cell Res 28(5):518–528 [PMID: 5951902]
18. Dibble CC, Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15(6):555–564 [PMID: 3743096]
19. Bracho-Valdés I et al (2011) mTORC1‐and mTORC2‐interacting proteins keep their multifunctional partners focused. IUBMB Life 63(10):896–914
20. Bond P (2016) Regulation of mTORC1 by growth factors, energy status, amino acids and mechanical stimuli at a glance. J Int Soc Sports Nutr 13(1):8 [PMID: 4774173]
21. Showkat M, Beigh MA, Andrabi KI (2014) mTOR signaling in protein translation regulation: implications in cancer genesis and therapeutic interventions. Mol Biol Int 2014:1–14
22. Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10(14):2305–2316 [PMID: 3322468]
23. Kaizuka T et al (2010) Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 285(26):20109–20116 [PMID: 2888423]
24. Chang L et al (2015) Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. Crit Rev Oncol Hematol 96(3):507–517
25. Edwards E et al (2002) Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 62(16):4671–4677
26. Schmidt-Ullrich RK et al (2003) ERBB receptor tyrosine kinases and cellular radiation responses. Oncogene 22(37):5855–5865
27. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35
28. Wang L et al (2016) Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo. Tumor Biol 37(9):11743–11752
29. Pan XD et al (2017) Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo. PloS ONE. https://doi.org/10.1371/journal.pone.0172555 [DOI: 10.1371/journal.pone.0172555]
30. Xing X et al (2014) PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway. Anti-Cancer Drugs 25(10):1129 [PMID: 4222793]
31. Huang H et al (2017) Two mTOR inhibitors, rapamycin and Torin 1, differentially regulate iron-induced generation of mitochondrial ROS. Biometals 30(6):975–980
32. Yongxi T et al (2015) Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular carcinoma cell activity in vitro and in vivo. Biochem Biophys Res Commun 465(3):494–500
33. Yu K et al (2009) Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69(15):6232–6240
34. Garcia-Echeverria C (2011) Blocking the mTOR pathway: a drug discovery perspective. Portland Press Ltd, London
35. Zhou H-Y, Huang S-L (2012) Current development of the second generation of mTOR inhibitors as anticancer agents. Chin J Cancer 31(1):8 [PMID: 3249493]
36. Mayer IA, Arteaga CL (2016) The PI3K/AKT pathway as a target for cancer treatment. Ann Rev Med 67:11–28
37. Rizzieri DA et al (2008) A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 14(9):2756–2762
38. Sinclair C et al (2017) mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation. Science 357(6355):1014–1021 [PMID: 5746055]
39. Eynott PR et al (2003) Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats. Immunology 109(3):461–467 [PMID: 1782985]
40. Chibana H et al (2017) Interleukin-1β is associated with coronary endothelial dysfunction in patients with mTOR-inhibitor-eluting stent implantation. Heart Vessels 32(7):823–832
41. Rini BI (2008) Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin Cancer Res 14(5):1286–1290
42. Liu Q et al (2009) mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg 6(2):47–55 [PMID: 2901551]
43. Alvarado Y et al (2011) Clinical activity of mammalian target of rapamycin inhibitors in solid tumors. Target Oncol 6(2):69–94
44. Tian T, Li X, Zhang J (2019) mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int J Mol Sci 20(3):755 [PMID: 6387042]
45. Tam SY, Wu VWC, Law HKW (2017) Influence of autophagy on the efficacy of radiotherapy. Radiat Oncol 12(1):57 [PMID: 5359955]
46. Yoo YJ et al (2017) An overview of rapamycin: from discovery to future perspectives. J Ind Microbiol Biotechnol 44(4–5):537–553
47. Weppler SA et al (2007) Response of U87 glioma xenografts treated with concurrent rapamycin and fractionated radiotherapy: possible role for thrombosis. Radiother Oncol 82(1):96–104
48. Dumont RA et al (2013) Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin. J Nucl Med 54(5):762–769
49. Eshleman JS et al (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62(24):7291–7297
50. Anandharaj A, Cinghu S, Park W-Y (2011) Rapamycin-mediated mTOR inhibition attenuates survivin and sensitizes glioblastoma cells to radiation therapy. Acta Biochim Biophys Sin 43(4):292–300
51. Buijsen J et al (2015) A phase I–II study on the combination of rapamycin and short course radiotherapy in rectal cancer. Radiother Oncol 116(2):214–220
52. Dancey JE, Curiel R, Purvis J (2009) Evaluating temsirolimus activity in multiple tumors: a review of clinical trials. Elsevier, Amsterdam
53. Ekshyyan O et al (2009) Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther 8(8):2255–2265 [PMID: 2758817]
54. Du Y, Peyser ND, Grandis JR (2014) Integration of molecular targeted therapy with radiation in head and neck cancer. Pharmacol Ther 142(1):88–98
55. Ushijima H et al (2015) Radio-sensitization effect of an mTOR inhibitor, temsirolimus, on lung adenocarcinoma A549 cells under normoxic and hypoxic conditions. J Radiat Res 56(4):663–668 [PMID: 4497394]
56. Cao C et al (2006) Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 66(20):10040–10047
57. Yu C-C et al (2014) RAD001 enhances the radiosensitivity of SCC4 oral cancer cells by inducing cell cycle arrest at the G2/M checkpoint. Anticancer Res 34(6):2927–2935
58. Kim KW et al (2008) Autophagy upregulation by inhibitors of caspase-3 and mTOR enhances radiotherapy in a mouse model of lung cancer. Autophagy 4(5):659–668
59. Gelsomino F et al (2017) A Dose-finding and biomarker evaluation phase Ib study of everolimus in association with 5-fluorouracil and pelvic radiotherapy as neoadjuvant treatment of locally advanced rectal cancer (E-LARC Study). Clin Colorectal Cancer 16(4):410-415.e1
60. Azria D et al (2013) Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: results of a phase I trial. J Clin Oncol 31(6_suppl):150–150
61. Narayan V et al (2017) Phase 1 trial of everolimus and radiation therapy for salvage treatment of biochemical recurrence in prostate cancer patients following prostatectomy. Int J Radiat Oncol Biol Phys 97(2):355–361
62. de Melo AC et al (2016) A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I. Cancer Chemother Pharmacol 78(1):101–109
63. Sarkaria JN et al (2011) North central cancer treatment group phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81(2):468–475
64. Ma DJ et al (2015) A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro Oncol 17(9):1261–1269
65. Chinnaiyan P et al (2018) A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG oncology RTOG 0913. Neuro Oncol 20(5):666–673
66. Deutsch E et al (2015) Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol 26(6):1223–1229
67. Prasad G et al (2011) Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide. Neuro Oncol 13(4):384–392 [PMID: 3064692]
68. Wen PY et al (2015) Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Neuro Oncol 17(9):1275–1283 [PMID: 4588757]
69. Gil del Alcazar, CR et al (2014) Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res 20(5):1235–1248
70. Cerniglia GJ et al (2012) Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol 82(6):1230–1240 [PMID: 3502620]
71. Gao M et al (2012) Dual PI3K/mTOR blockade by NVP-BEZ235 sensitizes head and neck squamous cell carcinoma to radiotherapy. Cancer Res. https://doi.org/10.1158/1538-7445 [DOI: 10.1158/1538-7445]
72. Chen YH et al (2015) Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer. Cancer Lett 357(2):582–590
73. Chen Y-H et al (2019) Maintenance BEZ235 treatment prolongs the therapeutic effect of the combination of BEZ235 and radiotherapy for colorectal cancer. Cancers 11(8):1204 [PMID: 6721476]
74. Chang L et al (2014) PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis 5(10):e1437–e1437 [PMID: 4237243]
75. Potiron VA et al (2013) Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions. Radiother Oncol 106(1):138–146
76. Zhu W, Fu W, Hu L (2013) NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, prominently enhances radiosensitivity of prostate cancer cell line PC-3. Cancer Biother Radiopharm 28(9):665–673
77. Kuger S et al (2014) Novel PI3K and mTOR inhibitor NVP-BEZ235 radiosensitizes breast cancer cell lines under normoxic and hypoxic conditions. Breast Cancer 8:39–49 [PMID: 3964191]
78. Wang WJ et al (2013) NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin 34(5):681–690 [PMID: 4002877]
79. Kuger S et al (2013) Radiosensitization of glioblastoma cell lines by the dual PI3K and mTOR inhibitor NVP-BEZ235 depends on drug-irradiation schedule. Transl Oncol 6(2):169-1N16 [PMID: 3610553]
80. Leiker AJ et al (2015) Radiation enhancement of head and neck squamous cell carcinoma by the dual PI3K/mTOR inhibitor PF-05212384. Clin Cancer Res 21(12):2792–2801 [PMID: 25724523]
81. Wilson GD et al (2021) Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer. Clin Transl Radiat Oncol 26:15–23 [PMID: 33251343]
82. Kahn J et al (2014) The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neurooncology 16(1):29–37
83. Hayman TJ et al (2014) The ATP-competitive mTOR inhibitor INK128 enhances in vitro and in vivo radiosensitivity of pancreatic carcinoma cells. Clin Cancer Res 20(1):110–119
84. Connolly E et al (2011) TORC1/2 inhibition with concurrent radiation controls inflammatory breast cancer in a preclinical animal model through selective blockade of translation. Int J Radiat Oncol Biol Phys 81(2):S751
85. Luo J et al (2018) Torin2 enhances the radiosensitivity of MCF–7 breast cancer cells by downregulating the mTOR signaling pathway and ATM phosphorylation. Mol Med Rep 17(1):366–373
86. Chang L et al (2019) A low dose of AZD8055 enhances radiosensitivity of nasopharyngeal carcinoma cells by activating autophagy and apoptosis. Am J Cancer Res 9(9):1922 [PMID: 6780664]
87. Shu H et al (2007) SF1126, a novel integrin-targeting phosphatidylinositol-3 kinase inhibitor, has radiosensitizing and anti-tumor effects in glioma model systems. Int J Radiat Oncol Biol Phys 69(3):S98
88. Chen Y et al (2015) Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer. Mol Med Rep 12(2):1645–1652 [PMID: 4464360]
89. Nakamura JL et al (2005) PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 71(3):215–222
90. Kao GD et al (2007) Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. J Biol Chem 282(29):21206–21212
91. Gupta AK et al (2003) Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys 56(3):846–853
92. Li HF, Kim JS, Waldman T (2009) Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol 4:43 [PMID: 2765447]
93. Bai R et al (2016) The effect of PI3K inhibitor LY294002 and gemcitabine hydrochloride combined with ionizing radiation on the formation of vasculogenic mimicry of Panc-1 cells in vitro and in vivo. Neoplasma 63(1):80–92
94. Raynaud FI et al (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 67(12):5840–5850
95. Prevo R et al (2008) Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res 68(14):5915–5923
96. Djuzenova CS et al (2016) Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: the role of drug-irradiation schedule. Oncotarget 7(25):38191–38209 [PMID: 5122382]
97. Liu T et al (2015) Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther 14(2):429–439
98. Xue Q et al (2008) Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res 68(22):9551–9557 [PMID: 2727940]
99. Diaz R et al (2009) The novel Akt inhibitor palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer 100(6):932–940 [PMID: 2661786]
100. Park JH et al (2017) Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer. Oncotarget 8(68):112893–112906 [PMID: 5762560]

MeSH Term

Chemicals