Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches

Author(s): Murat Ihlamur, Busra Akgul, Yağmur Zengin, Şenay Vural Korkut, Kübra Kelleci* and Emrah Şefik Abamor

Volume 24, Issue 4, 2024

Published on: 31 May, 2023

Page: [478 - 494] Pages: 17

DOI: 10.2174/1566524023666230509161645

Price: $65

Abstract

mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer.

This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles.

Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.

Keywords: mTOR, mTOR inhibitor, cancer, resistance mechanisms, nanoparticles, next-generation inhibitors, approaches.

« Previous Next »
[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Cree IA. Cancer biology. Methods Mol Biol 2011; 731: 1-11.
[http://dx.doi.org/10.1007/978-1-61779-080-5_1] [PMID: 21516393]
[3]
Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med 2015; 5(4): a006098.
[http://dx.doi.org/10.1101/cshperspect.a006098] [PMID: 25833940]
[4]
Panda M, Biswal BK. Cell signaling and cancer: A mechanistic insight into drug resistance. Mol Biol Rep 2019; 46(5): 5645-59.
[http://dx.doi.org/10.1007/s11033-019-04958-6] [PMID: 31280421]
[5]
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298(5600): 1912-34.
[http://dx.doi.org/10.1126/science.1075762] [PMID: 12471243]
[6]
Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010; 141(7): 1117-34.
[http://dx.doi.org/10.1016/j.cell.2010.06.011] [PMID: 20602996]
[7]
Paul MK, Mukhopadhyay AK. Tyrosine kinase-role and significance in cancer. Int J Med Sci 2004; 1(2): 101-15.
[http://dx.doi.org/10.7150/ijms.1.101] [PMID: 15912202]
[8]
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149(2): 274-93.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[9]
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
[http://dx.doi.org/10.1126/science.1106148] [PMID: 15718470]
[10]
Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497(7448): 217-23.
[http://dx.doi.org/10.1038/nature12122] [PMID: 23636326]
[11]
Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8(3): 224-36.
[http://dx.doi.org/10.1016/j.cmet.2008.07.007] [PMID: 18762023]
[12]
Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM, Manning BD. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 2016; 351(6274): 728-33.
[http://dx.doi.org/10.1126/science.aad0489] [PMID: 26912861]
[13]
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13(2): 132-41.
[http://dx.doi.org/10.1038/ncb2152] [PMID: 21258367]
[14]
Cloëtta D, Thomanetz V, Baranek C, et al. Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis. J Neurosci 2013; 33(18): 7799-810.
[http://dx.doi.org/10.1523/JNEUROSCI.3294-12.2013] [PMID: 23637172]
[15]
García-Martínez 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(3): 375-85.
[http://dx.doi.org/10.1042/BJ20081668] [PMID: 18925875]
[16]
Fruman DA, Rommel C. PI3K and cancer: Lessons, challenges and opportunities. Nat Rev Drug Discov 2014; 13(2): 140-56.
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[17]
Conciatori F, Ciuffreda L, Bazzichetto C, et al. mTOR cross-talk in cancer and potential for combination therapy. Cancers 2018; 10(1): 23.
[http://dx.doi.org/10.3390/cancers10010023] [PMID: 29351204]
[18]
Zhang Y, Kwok-Shing Ng P, Kucherlapati M, et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell 2017; 31(6): 820-32.
[http://dx.doi.org/10.1016/j.ccell.2017.04.013] [PMID: 28528867]
[19]
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009; 8(8): 627-44.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[20]
Zoncu R, Efeyan A, Sabatini DM. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12(1): 21-35.
[http://dx.doi.org/10.1038/nrm3025] [PMID: 21157483]
[21]
Pópulo H, Soares P, Faustino A, et al. mTOR pathway activation in cutaneous melanoma is associated with poorer prognosis characteristics. Pigment Cell Melanoma Res 2011; 24(1): 254-7.
[http://dx.doi.org/10.1111/j.1755-148X.2010.00796.x] [PMID: 21029395]
[22]
El-Hashemite N, Zhang H, Henske EP, Kwiatkowski DJ. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 2003; 361(9366): 1348-9.
[http://dx.doi.org/10.1016/S0140-6736(03)13044-9] [PMID: 12711473]
[23]
Grabiner BC, Nardi V, Birsoy K, et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov 2014; 4(5): 554-63.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0929] [PMID: 24631838]
[24]
Patel PH, Chadalavada RSV, Chaganti RSK, Motzer RJ. Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res 2006; 12(24): 7215-20.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-2254] [PMID: 17189392]
[25]
Feng W, Brown RE, Trung CD, et al. Morphoproteomic profile of mTOR, Ras/Raf kinase/ERK, and NF-kappaB pathways in human gastric adenocarcinoma. Ann Clin Lab Sci 2008; 38(3): 195-209.
[PMID: 18715846]
[26]
Xu MZ, Yao TJ, Lee NPY, et al. Yes-associated protein is an independent prognostic marker in hepatocellular carcinoma. Cancer 2009; 115(19): 4576-85.
[http://dx.doi.org/10.1002/cncr.24495] [PMID: 19551889]
[27]
Düvel K, Yecies JL, Menon S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39(2): 171-83.
[http://dx.doi.org/10.1016/j.molcel.2010.06.022] [PMID: 20670887]
[28]
Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146(3): 408-20.
[http://dx.doi.org/10.1016/j.cell.2011.06.034] [PMID: 21816276]
[29]
Ricoult SJH, Yecies JL, Ben-Sahra I, Manning BD. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 2016; 35(10): 1250-60.
[http://dx.doi.org/10.1038/onc.2015.179] [PMID: 26028026]
[30]
Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006; 441(7092): 424-30.
[http://dx.doi.org/10.1038/nature04869] [PMID: 16724053]
[31]
Vaira V, Lee CW, Goel HL, Bosari S, Languino LR, Altieri DC. Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 2007; 26(19): 2678-84.
[http://dx.doi.org/10.1038/sj.onc.1210094] [PMID: 17072337]
[32]
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100(25): 15077-82.
[http://dx.doi.org/10.1073/pnas.2436255100] [PMID: 14657337]
[33]
Degenhardt K, Mathew R, Beaudoin B, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10(1): 51-64.
[http://dx.doi.org/10.1016/j.ccr.2006.06.001] [PMID: 16843265]
[34]
Li J, Kim SG, Blenis J. Rapamycin: One drug, many effects. Cell Metab 2014; 19(3): 373-9.
[http://dx.doi.org/10.1016/j.cmet.2014.01.001] [PMID: 24508508]
[35]
Hasskarl J, Everolimus HJ. Recent Results Cancer Res 2018; 211: 101-23.
[http://dx.doi.org/10.1007/978-3-319-91442-8_8] [PMID: 30069763]
[36]
Kwitkowski VE, Prowell TM, Ibrahim A, et al. FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 2010; 15(4): 428-35.
[http://dx.doi.org/10.1634/theoncologist.2009-0178] [PMID: 20332142]
[37]
Hanna GJ, Busaidy NL, Chau NG, et al. Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: A phase II study. Clin Cancer Res 2018; 24(7): 1546-53.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-2297] [PMID: 29301825]
[38]
Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol 2013; 31(31): 3935-43.
[http://dx.doi.org/10.1200/JCO.2012.48.3552] [PMID: 24043745]
[39]
Korfel A, Schlegel U, Herrlinger U, et al. Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol 2016; 34(15): 1757-63.
[http://dx.doi.org/10.1200/JCO.2015.64.9897] [PMID: 26976424]
[40]
Bendell JC, Varghese AM, Hyman DM, et al. A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res 2018; 24(14): 3253-62.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-3421] [PMID: 29636360]
[41]
Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 2008; 7(7): 1851-63.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0017] [PMID: 18606717]
[42]
Knight SD, Adams ND, Burgess JL, et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of Rapamycin. ACS Med Chem Lett 2010; 1(1): 39-43.
[http://dx.doi.org/10.1021/ml900028r] [PMID: 24900173]
[43]
Yu P, Laird AD, Du X, et al. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway. Mol Cancer Ther 2014; 13(5): 1078-91.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0709] [PMID: 24634413]
[44]
Bendell JC, Kurkjian C, Infante JR, et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs 2015; 33(2): 463-71.
[http://dx.doi.org/10.1007/s10637-015-0218-6] [PMID: 25707361]
[45]
Britten CD, Adjei AA, Millham R, et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest New Drugs 2014; 32(3): 510-7.
[http://dx.doi.org/10.1007/s10637-013-0062-5] [PMID: 24395457]
[46]
Hsieh AC, Liu Y, Edlind MP, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485(7396): 55-61.
[http://dx.doi.org/10.1038/nature10912] [PMID: 22367541]
[47]
Mateo J, Olmos D, Dumez H, et al. A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. Br J Cancer 2016; 114(8): 889-96.
[http://dx.doi.org/10.1038/bjc.2016.59] [PMID: 27002938]
[48]
Bendell JC, Kelley RK, Shih KC, et al. A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma. Cancer 2015; 121(19): 3481-90.
[http://dx.doi.org/10.1002/cncr.29422] [PMID: 26177599]
[49]
Basu B, Dean E, Puglisi M, et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res 2015; 21(15): 3412-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-2422] [PMID: 25805799]
[50]
Ballou LM, Lin RZ. Rapamycin and mTOR kinase inhibitors. J Chem Biol 2008; 1(1-4): 27-36.
[http://dx.doi.org/10.1007/s12154-008-0003-5] [PMID: 19568796]
[51]
Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996; 273(5272): 239-42.
[http://dx.doi.org/10.1126/science.273.5272.239] [PMID: 8662507]
[52]
Hsieh AC, Costa M, Zollo O, et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 2010; 17(3): 249-61.
[http://dx.doi.org/10.1016/j.ccr.2010.01.021] [PMID: 20227039]
[53]
Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22(2): 159-68.
[http://dx.doi.org/10.1016/j.molcel.2006.03.029] [PMID: 16603397]
[54]
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med 2002; 8(2): 128-35.
[http://dx.doi.org/10.1038/nm0202-128] [PMID: 11821896]
[55]
Meng L, Zheng XFS. Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin 2015; 36(10): 1163-9.
[http://dx.doi.org/10.1038/aps.2015.68] [PMID: 26299952]
[56]
Carew JS, Kelly KR, Nawrocki ST. Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 2011; 6(1): 17-27.
[http://dx.doi.org/10.1007/s11523-011-0167-8] [PMID: 21547705]
[57]
Yao JC, Fazio N, Singh S, 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. Lancet 2016; 387(10022): 968-77.
[http://dx.doi.org/10.1016/S0140-6736(15)00817-X] [PMID: 26703889]
[58]
Schneider TC, de Wit D, Links TP, et al. Everolimus in patients with advanced follicular-derived thyroid cancer: Results of a phase II clinical trial. J Clin Endocrinol Metab 2017; 102(2): 698-707.
[PMID: 27870581]
[59]
Demetri GD, Chawla SP, Ray-Coquard I, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013; 31(19): 2485-92.
[http://dx.doi.org/10.1200/JCO.2012.45.5766] [PMID: 23715582]
[60]
Besse B, Leighl N, Bennouna J, et al. Phase II study of everolimus–erlotinib in previously treated patients with advanced non-small-cell lung cancer. Ann Oncol 2014; 25(2): 409-15.
[http://dx.doi.org/10.1093/annonc/mdt536] [PMID: 24368400]
[61]
Lew S, Chamberlain RS. Risk of metabolic complications in patients with solid tumors treated with mtor inhibitors: Meta-analysis. Anticancer Res 2016; 36(4): 1711-8.
[PMID: 27069150]
[62]
Colombo N, McMeekin DS, Schwartz PE, et al. Ridaforolimus as a single agent in advanced endometrial cancer: Results of a single-arm, phase 2 trial. Br J Cancer 2013; 108(5): 1021-6.
[http://dx.doi.org/10.1038/bjc.2013.59] [PMID: 23403817]
[63]
Yu K, Toral-Barza L, Shi C, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009; 69(15): 6232-40.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-0299] [PMID: 19584280]
[64]
Brown JR, Hamadani M, Hayslip J, et al. Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: an open-label, phase 2 trial. Lancet Haematol 2018; 5(4): e170-80.
[http://dx.doi.org/10.1016/S2352-3026(18)30030-9] [PMID: 29550382]
[65]
Rashid MM, Lee H, Jung BH. Metabolite identification and pharmacokinetic profiling of PP242, an ATP-competitive inhibitor of mTOR using ultra high-performance liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1072: 244-51.
[http://dx.doi.org/10.1016/j.jchromb.2017.11.027] [PMID: 29195143]
[66]
Badawi M, Kim J, Dauki A, et al. CD44 positive and sorafenib insensitive hepatocellular carcinomas respond to the ATP-competitive mTOR inhibitor INK128. Oncotarget 2018; 9(40): 26032-45.
[http://dx.doi.org/10.18632/oncotarget.25430] [PMID: 29899840]
[67]
Wong Te Fong AC, Thavasu P, Gagrica S, et al. Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models. Oncotarget 2017; 8(69): 113874-84.
[http://dx.doi.org/10.18632/oncotarget.23022] [PMID: 29371953]
[68]
Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: A new generation of mTOR inhibitors. Nat Rev Drug Discov 2011; 10(11): 868-80.
[http://dx.doi.org/10.1038/nrd3531] [PMID: 22037041]
[69]
Raynaud FI, Eccles SA, Patel S, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: From PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther 2009; 8(7): 1725-38.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-1200] [PMID: 19584227]
[70]
Chiarini F, Evangelisti C, McCubrey JA, Martelli AM. Current treatment strategies for inhibiting mTOR in cancer. Trends Pharmacol Sci 2015; 36(2): 124-35.
[http://dx.doi.org/10.1016/j.tips.2014.11.004] [PMID: 25497227]
[71]
Chen D, Lin X, Zhang C, et al. Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway. Cell Death Dis 2018; 9(2): 123.
[http://dx.doi.org/10.1038/s41419-017-0132-2] [PMID: 29374144]
[72]
Manara MC, Nicoletti G, Zambelli D, et al. NVP-BEZ235 as a new therapeutic option for sarcomas. Clin Cancer Res 2010; 16(2): 530-40.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0816] [PMID: 20068094]
[73]
Freitag H, et al. Inhibition of mTOR’s catalytic site by PKI-587 is a promising therapeutic option for gastroenteropancreatic neuroendocrine tumor disease. Neuroendocrinology 2016; 2016: 105.
[PMID: 27513674]
[74]
del Campo JM, Birrer M, Davis C, et al. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol 2016; 142(1): 62-9.
[http://dx.doi.org/10.1016/j.ygyno.2016.04.019] [PMID: 27103175]
[75]
Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 2008; 22(9): 1698-706.
[http://dx.doi.org/10.1038/leu.2008.144] [PMID: 18548104]
[76]
Rehan M. Anticancer compound XL765 as PI3K/mTOR dual inhibitor: A structural insight into the inhibitory mechanism using computational approaches. PLoS One 2019; 14(6): e0219180.
[http://dx.doi.org/10.1371/journal.pone.0219180] [PMID: 31247018]
[77]
Wang C, Gao D, Guo K, et al. Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model. BMC Cancer 2012; 12(1): 166.
[http://dx.doi.org/10.1186/1471-2407-12-166] [PMID: 22559167]
[78]
Simmons JK, Patel J, Michalowski A, et al. TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms. Mol Oncol 2014; 8(2): 261-72.
[http://dx.doi.org/10.1016/j.molonc.2013.11.007] [PMID: 24429254]
[79]
Miyata H, Ashizawa T, Iizuka A, et al. Combination of a STAT3 inhibitor and an mTOR inhibitor against a temozolomide-resistant glioblastoma cell line. Cancer Genomics Proteomics 2017; 14(1): 83-92.
[http://dx.doi.org/10.21873/cgp.20021] [PMID: 28031240]
[80]
Matsuki M. Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. Cancer Sci 2017; 108(4): 763-71.
[81]
Morise M, Taniguchi H, Saka H, et al. Phase II study of erlotinib for previously treated patients with EGFR wild-type non-small-cell lung cancer, following EGFR mutation status reevaluation with the Scorpion Amplified Refractory Mutation System. Mol Clin Oncol 2014; 2(6): 991-6.
[http://dx.doi.org/10.3892/mco.2014.354] [PMID: 25279187]
[82]
Bachelot T, Bourgier C, Cropet C, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 2012; 30(22): 2718-24.
[http://dx.doi.org/10.1200/JCO.2011.39.0708] [PMID: 22565002]
[83]
Christopoulos P, Engel-Riedel W, Grohé C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: A multicenter phase II trial. Ann Oncol 2017; 28(8): 1898-902.
[http://dx.doi.org/10.1093/annonc/mdx268] [PMID: 28535181]
[84]
Fishman MN, Srinivas S, Hauke RJ, et al. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur J Cancer 2013; 49(13): 2841-50.
[http://dx.doi.org/10.1016/j.ejca.2013.04.019] [PMID: 23726267]
[85]
1eiler M. Oral ridaforolimus plus trastuzumab for patients with HER2+ trastuzumab-refractory metastatic breast cancer. Clin Breast Cancer 2015; 15(1): 60-5.
[86]
Becker MN, Wu KJ, Marlow LA, et al. The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. Urol Oncol 2014; 32(3): 317-26.
[http://dx.doi.org/10.1016/j.urolonc.2013.06.002] [PMID: 24054871]
[87]
Kojima K, Shimanuki M, Shikami M, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia 2008; 22(9): 1728-36.
[http://dx.doi.org/10.1038/leu.2008.158] [PMID: 18548093]
[88]
Mohan S, Vander Broek R, Shah S, et al. MEK inhibitor PD-0325901 overcomes resistance to PI3K/mTOR inhibitor PF-5212384 and potentiates antitumor effects in human head and neck squamous cell carcinoma. Clin Cancer Res 2015; 21(17): 3946-56.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3377] [PMID: 25977343]
[89]
Jänne PA, Cohen RB, Laird AD, et al. Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J Thorac Oncol 2014; 9(3): 316-23.
[http://dx.doi.org/10.1097/JTO.0000000000000088] [PMID: 24496004]
[90]
Chen SM, Guo CL, Shi JJ, et al. HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer. Int J Cancer 2014; 135(10): 2462-74.
[http://dx.doi.org/10.1002/ijc.28880] [PMID: 24706460]
[91]
Hai J, Liu S, Bufe L, et al. Synergy of WEE1 and mTOR inhibition in mutant KRAS -driven lung cancers. Clin Cancer Res 2017; 23(22): 6993-7005.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-1098] [PMID: 28821559]
[92]
Liang X, Li D, Leng S, Zhu X. RNA-based pharmacotherapy for tumors: From bench to clinic and back. Biomed Pharmacother 2020; 125: 109997.
[http://dx.doi.org/10.1016/j.biopha.2020.109997] [PMID: 32062550]
[93]
Lasithiotakis KG, Sinnberg TW, Schittek B, et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Invest Dermatol 2008; 128(8): 2013-23.
[http://dx.doi.org/10.1038/jid.2008.44] [PMID: 18323781]
[94]
Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015; 16(15): 1473-82.
[http://dx.doi.org/10.1016/S1470-2045(15)00290-9] [PMID: 26482279]
[95]
Kim ST, Kim SY, Klempner SJ, et al. Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition. Ann Oncol 2017; 28(3): 547-54.
[http://dx.doi.org/10.1093/annonc/mdw669] [PMID: 28028034]
[96]
Kim SJ, Shin DY, Kim JS, et al. A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas. Ann Oncol 2016; 27(4): 712-8.
[http://dx.doi.org/10.1093/annonc/mdv624] [PMID: 26861608]
[97]
Hurvitz SA, Dalenc F, Campone M, et al. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. Breast Cancer Res Treat 2013; 141(3): 437-46.
[http://dx.doi.org/10.1007/s10549-013-2689-5] [PMID: 24101324]
[98]
Harzstark AL, Small EJ, Weinberg VK, et al. A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer 2011; 117(18): 4194-200.
[http://dx.doi.org/10.1002/cncr.25931] [PMID: 21387258]
[99]
Kyriakopoulos CE, Braden AM, Kolesar JM, et al. A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors. Invest New Drugs 2017; 35(3): 290-7.
[http://dx.doi.org/10.1007/s10637-016-0418-8] [PMID: 28004284]
[100]
Kim MN, Lee SM, Kim JS, Hwang SG. Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma. Cancer Chemother Pharmacol 2019; 84(4): 809-17.
[http://dx.doi.org/10.1007/s00280-019-03918-y] [PMID: 31385002]
[101]
Inaba K, Oda K, Ikeda Y, et al. Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas. Gynecol Oncol 2015; 138(2): 323-31.
[http://dx.doi.org/10.1016/j.ygyno.2015.05.031] [PMID: 26033306]
[102]
Zaidi AH, Kosovec JE, Matsui D, et al. PI3K/mTOR dual inhibitor, LY3023414, demonstrates potent antitumor efficacy against esophageal adenocarcinoma in a rat model. Ann Surg 2017; 266(1): 91-8.
[http://dx.doi.org/10.1097/SLA.0000000000001908] [PMID: 27471841]
[103]
Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res 2009; 315(3): 485-97.
[http://dx.doi.org/10.1016/j.yexcr.2008.11.007] [PMID: 19071109]
[104]
Rodrik-Outmezguine VS, Okaniwa M, Yao Z, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 2016; 534(7606): 272-6.
[http://dx.doi.org/10.1038/nature17963] [PMID: 27279227]
[105]
Kuroshima K, Yoshino H, Okamura S, et al. Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor, against sunitinib‐resistant renal cell carcinoma. Cancer Sci 2020; 111(5): 1607-18.
[http://dx.doi.org/10.1111/cas.14395] [PMID: 32232883]
[106]
Li QL, Gu FM, Wang Z, et al. Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma. PLoS One 2012; 7(3): e33379.
[http://dx.doi.org/10.1371/journal.pone.0033379] [PMID: 22428038]
[107]
Raimondo L, D’Amato V, Servetto A, et al. Everolimus induces met inactivation by disrupting the FKBP12/Met complex. Oncotarget 2016; 7(26): 40073-84.
[http://dx.doi.org/10.18632/oncotarget.9484] [PMID: 27223077]
[108]
Lin F, de Gooijer MC, Hanekamp D, et al. PI3K–mTOR pathway inhibition exhibits efficacy against high-grade glioma in clinically relevant mouse models. Clin Cancer Res 2017; 23(5): 1286-98.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1276] [PMID: 27553832]
[109]
Wu CP, Murakami M, Hsiao SH, et al. Overexpression of ATP-binding cassette subfamily G member 2 Confers resistance to Phosphatidylinositol 3-Kinase inhibitor PF-4989216 in cancer cells. Mol Pharm 2017; 14(7): 2368-77.
[http://dx.doi.org/10.1021/acs.molpharmaceut.7b00277] [PMID: 28597653]
[110]
Fourneaux B, Bourdon A, Dadone B, et al. Identifying and targeting cancer stem cells in leiomyosarcoma: Prognostic impact and role to overcome secondary resistance to PI3K/mTOR inhibition. J Hematol Oncol 2019; 12(1): 11-.
[http://dx.doi.org/10.1186/s13045-018-0694-1] [PMID: 30683135]
[111]
Bhola NE, Jansen VM, Koch JP, et al. Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and notch-dependent cancer stem cell population. Cancer Res 2016; 76(2): 440-52.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1640-T] [PMID: 26676751]
[112]
Hoxhaj G, Hughes-Hallett J, Timson RC, et al. The mTORC1 signaling network senses changes in cellular purine nucleotide levels. Cell Rep 2017; 21(5): 1331-46.
[http://dx.doi.org/10.1016/j.celrep.2017.10.029] [PMID: 29091770]
[113]
Graff JR, Konicek BW, Carter JH, Marcusson EG. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 2008; 68(3): 631-4.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5635] [PMID: 18245460]
[114]
Wang J, Ye Q, Cao Y, et al. Snail determines the therapeutic response to mTOR kinase inhibitors by transcriptional repression of 4E-BP1. Nat Commun 2017; 8(1): 2207.
[http://dx.doi.org/10.1038/s41467-017-02243-3] [PMID: 29263324]
[115]
D’Abronzo LS, Bose S, Crapuchettes ME, et al. The androgen receptor is a negative regulator of eIF4E phosphorylation at S209: implications for the use of mTOR inhibitors in advanced prostate cancer. Oncogene 2017; 36(46): 6359-73.
[http://dx.doi.org/10.1038/onc.2017.233] [PMID: 28745319]
[116]
Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem 1995; 270(46): 27531-7.
[http://dx.doi.org/10.1074/jbc.270.46.27531] [PMID: 7499212]
[117]
Fruman DA, Wood MA, Gjertson CK, Katz HR, Burakoff SJ, Bierer BE. FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells. Eur J Immunol 1995; 25(2): 563-71.
[http://dx.doi.org/10.1002/eji.1830250239] [PMID: 7533090]
[118]
Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009; 284(12): 8023-32.
[http://dx.doi.org/10.1074/jbc.M900301200] [PMID: 19150980]
[119]
Fan Q, Aksoy O, Wong RA, et al. A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma. Cancer Cell 2017; 31(3): 424-35.
[http://dx.doi.org/10.1016/j.ccell.2017.01.014] [PMID: 28292440]
[120]
Lawrence MS, Stojanov P, Mermel CH, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505(7484): 495-501.
[http://dx.doi.org/10.1038/nature12912] [PMID: 24390350]
[121]
Park YL, Kim HP, Cho YW, et al. Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations. Int J Cancer 2019; 144(2): 389-401.
[http://dx.doi.org/10.1002/ijc.31662] [PMID: 29978469]
[122]
Yang C, Huang X, Liu H, et al. PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242. Oncotarget 2017; 8(24): 39185-97.
[http://dx.doi.org/10.18632/oncotarget.16642] [PMID: 28402933]
[123]
Neklesa TK, Davis RW. Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex. Proc Natl Acad Sci 2008; 105(39): 15166-71.
[http://dx.doi.org/10.1073/pnas.0807712105] [PMID: 18812505]
[124]
Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10(6): 594-601.
[http://dx.doi.org/10.1038/nm1052] [PMID: 15156201]
[125]
Tukmachev D, Lunov O, Zablotskii V, et al. An effective strategy of magnetic stem cell delivery for spinal cord injury therapy. Nanoscale 2015; 7(9): 3954-8.
[http://dx.doi.org/10.1039/C4NR05791K] [PMID: 25652717]
[126]
Zhang L, Zhai BZ, Wu YJ, Wang Y. Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment. Drug Deliv 2023; 30(1): 1-18.
[http://dx.doi.org/10.1080/10717544.2022.2144541] [PMID: 36597205]
[127]
Loos C, Syrovets T, Musyanovych A, Mailänder V, Landfester K, Simmet T. Amino-functionalized nanoparticles as inhibitors of mTOR and inducers of cell cycle arrest in leukemia cells. Biomaterials 2014; 35(6): 1944-53.
[http://dx.doi.org/10.1016/j.biomaterials.2013.11.056] [PMID: 24331713]
[128]
Li C, Liu H, Sun Y, et al. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. J Mol Cell Biol 2009; 1(1): 37-45.
[http://dx.doi.org/10.1093/jmcb/mjp002] [PMID: 19516051]
[129]
Khan MI, Mohammad A, Patil G, Naqvi SAH, Chauhan LKS, Ahmad I. Induction of ROS, mitochondrial damage and autophagy in lung epithelial cancer cells by iron oxide nanoparticles. Biomaterials 2012; 33(5): 1477-88.
[http://dx.doi.org/10.1016/j.biomaterials.2011.10.080] [PMID: 22098780]
[130]
Juan J, Cheng L, Shi M, Liu Z, Mao X. Poly-(allylamine hydrochloride)-coated but not poly(acrylic acid)-coated upconversion nanoparticles induce autophagy and apoptosis in human blood cancer cells. J Mater Chem B Mater Biol Med 2015; 3(28): 5769-76.
[http://dx.doi.org/10.1039/C5TB00646E] [PMID: 32262573]
[131]
Liu H-L, Zhang Y-L, Yang N, et al. A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt–TSC2-mTOR signaling. Cell Death Dis 2011; 2(5): e159.
[http://dx.doi.org/10.1038/cddis.2011.27] [PMID: 21593791]
[132]
Lunova M, Prokhorov A, Jirsa M, et al. Nanoparticle core stability and surface functionalization drive the mTOR signaling pathway in hepatocellular cell lines. Sci Rep 2017; 7(1): 16049.
[http://dx.doi.org/10.1038/s41598-017-16447-6] [PMID: 29167516]
[133]
Au KM, Wang AZ, Park SI. Pretargeted delivery of PI3K/mTOR small-molecule inhibitor–loaded nanoparticles for treatment of non-Hodgkin’s lymphoma. Sci Adv 2020; 6(14): eaaz9798.
[http://dx.doi.org/10.1126/sciadv.aaz9798] [PMID: 32270047]
[134]
Tang X, Li A, Xie C, et al. RETRACTED ARTICLE: The PI3K/mTOR dual inhibitor BEZ235 nanoparticles improve radiosensitization of hepatoma cells through apoptosis and regulation DNA repair pathway. Nanoscale Res Lett 2020; 15(1): 63.
[http://dx.doi.org/10.1186/s11671-020-3289-z] [PMID: 32219609]
[135]
Amin A, Eong S, Gillick J, et al. Targeting the mTOR pathway using novel ATP competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma. Int J Oncol 2021; 59(4): 83.
[http://dx.doi.org/10.3892/ijo.2021.5263] [PMID: 34523696]
[136]
Chresta CM, Davies BR, Hickson I, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010; 70(1): 288-98.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1751] [PMID: 20028854]

Rights & Permissions Print Cite
Article Metrics
20
2
© 2024 Bentham Science Publishers | Privacy Policy