MTOR inhibitors in cancer therapy

Xie, Jianling; Wang, Xuemin; Proud, Christopher G.

doi:10.12688/f1000research.9207.1

Cited by 268PI3K/AKT/mTOR signaling in cancerAdvanced Breast Cancer TherapiesMetabolism, Diabetes, and Cancer

MTOR inhibitors in cancer therapy

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Xie, Jianling, Wang, Xuemin, Proud, Christopher G.·2016·F1000Research

DOI 10.12688/f1000research.9207.1PMC PMC5007757

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Abstract

The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways and is accordingly hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy. However, progress in using inhibitors of mTOR signaling as therapeutic agents in oncology has been limited by a number of factors, including the fact that the classic mTOR inhibitor, rapamycin, inhibits only some of the effects of mTOR; the existence of several feedback loops; and the crucial importance of mTOR in normal physiology.

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Rapamycin can prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.
“Rapamycin can also prolong the life cycle of many species as diverse as worms and mice, and its signaling system has been implicated as the master regulator of cellular growth and metabolism.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [236]
A family of molecules that are the mechanistic target of the rapamycin (mTOR) complex has been attributed a major role in the biology of cell metabolism, growth, longevity, and even preterm birth.
“A family of molecules that are the mechanistic target of the rapamycin (mTOR) complex has been attributed a major role in the biology of cell metabolism, growth, longevity, and even preterm birth(230–236).”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [236]

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Geoerger, B., Kerr, K., Tang, C. B., Fung, K., Powell, B., Sutton, L. N., Phillips∥, P. C., & Janss, A. J. (2001) · PubMed · Cited by 263 · see citing works
mTORC1 signaling controls multiple steps in ribosome biogenesis
Iadevaia, V., Liu, R., & Proud, C. G. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.08.004 · Cited by 248 · see citing works
SDZ RAD, A NEW RAPAMYCIN DERIVATIVE
Schuurman, H., Cottens, S., Fuchs, S., Joergensen, J., Meerloo, T., Sedrani, R. C., Tanner, M., Zenke, G., & Schüler, W. (1997) · Transplantation · doi:10.1097/00007890-199707150-00007 · Cited by 248 · cited 1× · see citing works
“For example, RAD001 (everolimus) 32,33 , developed by Novartis as an immuno-suppressive and anti-cancer drug (Table 1), is a hydroxyethyl ether-derivative.”
Background
Signalling to eIF4E in cancer
Siddiqui, N., & Sonenberg, N. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150126 · Cited by 220 · see citing works
Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer
Sato, T., Nakashima, A., Guo, L., Coffman, K., & Tamanoi, F. (2010) · Oncogene · doi:10.1038/onc.2010.28 · Cited by 214 · see citing works
Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR
Liu, Q., Xu, C., Kirubakaran, S., Zhang, X., Hur, W., Liu, Y., Kwiatkowski, N. P., Wang, J., Westover, K. D., Gao, P., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-1702 · Cited by 212 · see citing works
Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014
Pike, K. G., Malagu, K., Hummersone, M., Menear, K. A., Duggan, H. M. E., Gomez, S., Martin, N. M. B., Ruston, L., Pass, S. L., & Pass, M. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.01.019 · Cited by 210 · cited 1× · see citing works
“Moreover, AZD8055 and AZD2014 50,51 are two orally bioavailable compounds derived from the Ku compounds.”
Background
Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells
Carayol, N., Vakana, E., Sassano, A., Kaur, S., Goussetis, D. J., Glaser, H., Druker, B. J., Donato, N. J., Altman, J. K., Barr, S. M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005114107 · Cited by 179 · see citing works
Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation.
BAKER, H., SIDOROWICZ, A., Sehgal, S. N., & Vézina, C. (1978) · The Journal of Antibiotics · doi:10.7164/antibiotics.31.539 · Cited by 168 · see citing works
Rapamycin Has a Deleterious Effect on MIN-6 Cells and Rat and Human Islets
Bell, E., Cao, X., Moibi, J. A., Greene, S. R., Young, R., Trucco, M. M., Gao, Z., Matschinsky, F. M., Deng, S., Markman, J. F., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2731 · Cited by 165 · see citing works
TORC2 Structure and Function
Gaubitz, C., Prouteau, M., Kuśmider, B., & Loewith, R. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.04.001 · Cited by 160 · cited 1× · see citing works
“…other links from mTORC1 to the activation of protein synthesis and to the production of ribosomes 9,10 . mTORC2 has distinct substrates from mTORC1 11 , which include AKT (PKB) 12 , a protein kinase that is involved in anabolic signaling (for example, in the activation of mTORC1 13–15 and in cell…”
Background
The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia
Willems, L., Chapuis, N., Puissant, A., Maciel, T. T., Green, A. S., Jacque, N., Vignon, C., Park, S., Guichard, S. M., Hérault, O., et al. (2011) · Leukemia · doi:10.1038/leu.2011.339 · Cited by 159 · see citing works
Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function
Zhang, N., Su, D., Qu, S., Tse, T. E., Bottino, R., Balamurugan, A. N., Xu, J., Bromberg, J. S., & Dong, H. H. (2006) · Diabetes · doi:10.2337/db06-0173 · Cited by 158 · see citing works
eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies
Alain, T., Morita, M., Fonseca, B. D., Yanagiya, A., Siddiqui, N., Bhat, M., Zammit, D., Marcus, V., Metrakos, P. P., Voyer, L.-A., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2395 · Cited by 158 · cited 1× · see citing works
“One of the key targets for control by mTORC1, eIF4E, is often expressed at high levels in tumors 8 ; if its levels exceed those of its mTORC1-regulated inhibitors, 4E-BPs, then inhibition of mTORC1 will not be effective in restricting eIF4E function 60 .”
Background
mTORC1 signalling and mRNA translation
Proud, C. G. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370227 · Cited by 131 · cited 1× · see citing works
“There are two genes in mammals, often termed S6K1 and S6K2 , each of which gives rise to two protein isoforms 63 .”
Background
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Devlin, J. R., Hannan, K. M., Hein, N., Cullinane, C. M., Kusnadi, E. P., Ng, P. Y., George, A. J., Shortt, J., Bywater, M. J., Poortinga, G., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0673 · Cited by 127 · cited 1× · see citing works
“Bywater et al . have developed an inhibitor of Pol I, CX-5461 70 , which, when used in combination with everolimus, extended the survival of mice with myc-driven lymphoma 71 .”
Method
Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases
Liu, R., & Proud, C. G. (2016) · Acta Pharmacologica Sinica · doi:10.1038/aps.2015.123 · Cited by 117 · cited 1× · see citing works
“Inhibition of mTORC1 will also activate its downstream effector, eukaryotic elongation factor 2 kinase (eEF2K), which can promote cell survival 27 .”
Background
Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action.
Singh, K., Sun, S., & Vézina, C. (1979) · The Journal of Antibiotics · doi:10.7164/antibiotics.32.630 · Cited by 95 · see citing works
Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis
Iadevaia, V., Huo, Y., Zhang, Z., Foster, L. J., & Proud, C. G. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110682 · Cited by 92 · see citing works
Inhibition of mTOR Kinase by AZD8055 Can Antagonize Chemotherapy-induced Cell Death through Autophagy Induction and Down-regulation of p62/Sequestosome 1
Huang, S., Yang, Z. J., Yu, C., & Sinicrope, F. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.297432 · Cited by 90 · cited 1× · see citing works
“Indeed, AZD8055 is shown to activate autophagic flux in a variety of cancer cells 50,57,58 and the inhibition of autophagy was able to reverse the paradoxical cytoprotective effect of AZD8055 on colon carcinoma cells 57 .”
Background
Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway
Yu, P., Laird, A., Du, X., Wu, J., Won, K., Yamaguchi, T., Hsu, P. P., Qian, F., Jaeger, C. T., Zhang, W., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0709 · Cited by 82 · cited 1× · see citing works
“Other examples from this class of inhibitors include GSK2126458 from GlaxoSmithKline 38 , XL765 from Sanofi-Aventis and Exelixis 39 , and SF1126 from Semafore 40 .”
Background
The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase
Malagu, K., Duggan, H. M. E., Menear, K. A., Hummersone, M., Gomez, S., Bailey, C., Edwards, P., Drzewiecki, J., Leroux, F. R., Quesada, M. J., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.08.038 · Cited by 80 · cited 1× · see citing works
“Ku-0063794 and Ku-0068650 47,48 , developed by KuDOS Pharmaceuticals (now part of AstraZeneca), are also examples of early ATP-competitive mTOR inhibitors which exhibit great anti-proliferative potential against cancer cells in vitro .”
Background
Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2)
Barlow, A. D., Xie, J., Moore, C. E., Campbell, S. C., Shaw, J., Nicholson, M. L., & Herbert, T. P. (2012) · Diabetologia · doi:10.1007/s00125-012-2475-7 · Cited by 78 · cited 2× · see citing works
“…islet transplantations 52 , yet a follow-up study 5 years later has demonstrated that only approximately 10% of the recipients remained insulin independent 53 , likely owing to the fact that mTOR inhibitors would induce pancreatic β -cell death 54,55 as a result of the inhibition of mTORC2 56 .”
Background
Vertical Targeting of the Phosphatidylinositol-3 Kinase Pathway as a Strategy for Treating Melanoma
Aziz, S. A., Jilaveanu, L. B., Zito, C. R., Camp, R. L., Rimm, D. L., Conrad, P. J., & Kluger, H. M. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1490 · Cited by 78 · cited 1× · see citing works
“Not only does the dual mTOR/PI3K inhibitor NVP-BEZ235 exert potent anti-tumor activity in vivo but its effect can be further enhanced by the combination with inhibitors against other mitogenic pathways, such as the MEK/ERK inhibitors 36,37 .”
Background
Point mutations of the mTOR-RHEB pathway in renal cell carcinoma
Ghosh, A. P., Marshall, C. B., Coric, T., Shim, E., Kirkman, R. L., Ballestas, M. E., Ikura, M., Bjornsti, M., & Sudarshan, S. (2015) · Oncotarget · doi:10.18632/oncotarget.4963 · Cited by 77 · cited 2× · see citing works
“A final issue compromising the efficacy of mTOR inhibitors is that a wide range 72–76 of clinically relevant mutations in mTOR can increase the catalytic activity of mTOR and thus both mTORC1 and mTORC2, thereby reducing the effectiveness of such compounds toward the first two generations of mTOR…”
Background
Signaling crosstalk between the mTOR complexes
Xie, J., & Proud, C. G. (2014) · Translation · doi:10.4161/trla.28174 · Cited by 58 · see citing works
The SIN1-PH Domain Connects mTORC2 to PI3K
Yuan, H., & Guan, K. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1125 · Cited by 57 · cited 1× · see citing works
“It may be linked to the PI3K pathway 17 , which is frequently dysregulated in cancer, for example, by loss of the tumor suppressor protein PTEN (phosphatase and tensin homolog).”
Background
Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle
Rosner, M., Fuchs, C., Siegel, N., Valli, A., & Hengstschläger, M. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp271 · Cited by 55 · see citing works
Rapamycin induces transactivation of the EGFR and increases cell survival
Chaturvedi, D., Gao, X., Cohen, M. S., Taunton, J., & Patel, T. B. (2009) · Oncogene · doi:10.1038/onc.2008.490 · Cited by 52 · cited 1× · see citing works
“…F2108L ) confer resistance to rapalogs (first generation), and a kinase domain mutation (mTOR M2327I ) renders resistance to mTOR-KIs (second generation). mTOR, mammalian target of rapamycin. various feedback loops which, for example, promote activation of the oncogenic PI3K/Akt pathway 24,25 .”
Background
Differing effects of rapamycin and mTOR kinase inhibitors on protein synthesis
Huo, Y., Iadevaia, V., & Proud, C. G. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390446 · Cited by 45 · see citing works
Targeting Eukaryotic Translation in Mesothelioma Cells with an eIF4E-Specific Antisense Oligonucleotide
Jacobson, B. A., Thumma, S. C., Jay-Dixon, J., Patel, M. R., Kroening, K. D., Kratzke, M. G., Etchison, R. G., Konicek, B. W., Graff, J. R., & Kratzke, R. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081669 · Cited by 37 · cited 1× · see citing works
“Alternative ways of impairing eIF4E function may be effective in such settings; possibilities include the use of anti-sense RNAs against its mRNA 61 , and blocking its binding to its partner eIF4G 62 .”
Background
Structural insights of mTOR complex 1
Yuan, H., & Guan, K. (2016) · Cell Research · doi:10.1038/cr.2016.10 · Cited by 35 · cited 1× · see citing works
“DI NVP-BEZ235 (dactolisib) Phase I/II (22) Novartis MBC/pNET 35”

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Sorted by citations

Hallmarks of Cellular Senescence
Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.001 · Cited by 2,605 · see citing works
“Interestingly, major life-extending compounds, such as rapamycin, resveratrol, and metformin, have been shown with variable degree of confidence to reduce the SASP [97,159].”
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138 · see citing works
PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside
Alzahrani, A. S. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.009 · Cited by 1,063 · see citing works
Gastric cancer: a comprehensive review of current and future treatment strategies
Sexton, R. E., Hallak, M. N. A., Diab, M., & Azmi, A. S. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09925-3 · Cited by 776 · see citing works
The role of ubiquitination in tumorigenesis and targeted drug discovery
Deng, L., Meng, T., Chen, L., Wei, W., & Wang, P. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0107-0 · Cited by 744 · see citing works
Autophagy: The spotlight for cellular stress responses
Ravanan, P., Florance, I., & Talwar, P. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.08.029 · Cited by 578 · see citing works
Pathway Based Analysis of Mutation Data Is Efficient for Scoring Target Cancer Drugs
Zolotovskaia, M., Sorokin, M., Emelianova, A. A., Borisov, N., Kuzmin, D., Borger, P., Garazha, A., & Buzdin, A. A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00001 · Cited by 531 · see citing works
“, 2010), mTOR inhibitors (Xie et al., 2016), hormone receptors (Ko and Balk, 2004), proteasomal components (Kisselev et al.”
Background
Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment
Teleanu, R. I., Chircov, C., Grumezescu, A. M., & Teleanu, D. M. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm9010084 · Cited by 508 · see citing works
Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence
Almansour, N. M. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.836417 · Cited by 408 · see citing works
“(Xie et al., 2016; Medina et al., 2020). and improving free survival rate of TNBC patients (Reis-Filho and Tutt, 2008; Yu and Di, 2017).”
Influential
Modulating Glycolysis to Improve Cancer Therapy
Chelakkot, C., Chelakkot, V. S., Shin, Y. K., & Song, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032606 · Cited by 378 · see citing works
“Owing to their inhibitory effects, several rapamycin analogs have been approved for treating cancers [231,232].”
Background
The intracellular signalosome of PD-L1 in cancer cells
Escors, D., Gato, M., Zuazo, M., Arasanz, H., García-Granda, M. J., Vera, R., & Kochan, G. T. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0022-9 · Cited by 299 · see citing works
Signaling pathways in cancer metabolism: mechanisms and therapeutic targets
You, M., Xie, Z., Zhang, N., Zhang, Y., Xiao, D., Liu, S., Zhuang, W., Li, L., & Tao, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01442-3 · Cited by 297 · see citing works
“Of all 97 human cancers, mTORC1 is considered to be up-regulated by approximately 70%.(121) It has newly been reported to relate to acute myeloid leukemia,(317) subependymal giant cell astrocytoma,(318) triple-negative breast cancer(319) and pancreatic tumor.”
Background
Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response
Hombach‐Klonisch, S., Mehrpour, M., Shojaei, S., Harlos, C. H., Pitz, M. W., Hamaï, A., Siemianowicz, K., Likus, W., Wiecheć, E., Toyota, B. D., et al. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.017 · Cited by 290 · see citing works
Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity
Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B. H., & Grossman, L. I. (2017) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2017.06.003 · Cited by 253 · see citing works
The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
Woodcock, H. V., Eley, J. D., Guillotin, D., Platé, M., Nanthakumar, C. B., Martufi, M., Peace, S., Joberty, G., Poeckel, D., Good, R. B., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-07858-8 · Cited by 224 · see citing works
Recent advances and limitations of mTOR inhibitors in the treatment of cancer
Ali, E. S., Mitra, K., Akter, S., Ramproshad, S., Mondal, B., Khan, I. N., Islam, M. T., Sharifi‐Rad, J., Călina, D. C., & Cho, W. C. S. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02706-8 · Cited by 213 · see citing works
“Though rapamycin does not directly interact with mTORC2, attaching with mTOR in a complex form with FKBP12, it can indirectly affect mTORC2 [114].”
Background
Metabolite sensing and signaling in cell metabolism
Wang, Y.-P., & Lei, Q. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0024-7 · Cited by 205 · see citing works
The Translational Regulation in mTOR Pathway
Yang, M., Lu, Y., Piao, W., & Jin, H. (2022) · Biomolecules · doi:10.3390/biom12060802 · Cited by 206 · see citing works
“Therefore, so much attention has been devoted to understanding mTOR signaling pathway and to developing therapies that target this pathway [27].”
Background
Neuroinflammatory targets and treatments for epilepsy validated in experimental models
Aronica, E., Bauer, S., Bozzi, Y., Caleo, M., Dingledine, R. J., Gorter, J. A., Henshall, D. C., Kaufer, D., Koh, S., Löscher, W., et al. (2017) · Epilepsia · doi:10.1111/epi.13783 · Cited by 194 · see citing works
Kinases and Cancer
Cicenas, J., Žalytė, E., Bairoch, A., & Gaudet, P. (2018) · Cancers · doi:10.3390/cancers10030063 · Cited by 180 · see citing works
A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs
Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D., & Kaeberlein, M. R. (2017) · GeroScience · doi:10.1007/s11357-017-9972-z · Cited by 167 · see citing works
“Rapamycin is also used clinically for some rare forms of cancer (Xie et al. 2016), to treat tuberous sclerosis complex, and in cardiac stents, to prevent restenosis (Kaeberlein 2013).”
Background
Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations
Adebayo Michael, A. O., Ko, S., Tao, J., Moghe, A., Yang, H., Xu, M., Russell, J. O., Pradhan-Sundd, T., Liu, S., Singh, S., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.002 · Cited by 155 · see citing works
“New second and third generation mTORC1 inhibitors with greater potency may be more efficacious (Xie et al., 2016).”
Background
mTOR Cross-Talk in Cancer and Potential for Combination Therapy
Conciatori, F., Ciuffreda, L., Bazzichetto, C., Falcone, I., Pilotto, S., Bria, E., Cognetti, F., & Milella, M. (2018) · Cancers · doi:10.3390/cancers10010023 · Cited by 140 · see citing works
“Given the many oncogenes or tumor suppressors linked to mTOR signaling, it is estimated that mTORC1 function might be hyperactivated in up to 70% of all human tumors; much less information is available for mTORC2, although its link to PI3K/Phosphatase and tensin homolog on chromosome 10 (PTEN) suggests that it is also…”
Background
Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies
Rathore, R., & Tine, B. A. V. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10061182 · Cited by 122 · see citing works
Lysosomotropic drugs activate TFEB via lysosomal membrane fluidization and consequent inhibition of mTORC1 activity
Zhitomirsky, B., Yunaev, A., Kreiserman, R., Kaplan, A., Stark, M., & Assaraf, Y. G. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1227-0 · Cited by 119 · see citing works
Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions
Gala, U., Miller, D. A., & Williams, R. O. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.188319 · Cited by 118 · see citing works
Medication-Related Osteonecrosis of the Jaw (MRONJ): A Review of Pathophysiology, Risk Factors, Preventive Measures and Treatment Strategies
AlRowis, R., Aldawood, A., Alotaibi, M. D., Alnasser, E., AlSaif, I., Aljaber, A., & Natto, Z. S. (2022) · The Saudi Dental Journal · doi:10.1016/j.sdentj.2022.01.003 · Cited by 116 · see citing works
“…described MRONJ development in patients undergoing raloxifene therapy, but the patient also has a history of oral bisphosphonate (Bennardo et al., 2020b; King et al., 2019; Bindakhil and Mupparapu, 2018; Ebker et al., 2013; Fusco et al., 2016; Kim et al., 2013; Baur et al., 2015; Xie et al., 2016).”
Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity
Wright, S. C. E., Vasilevski, N., Serra, V., Rodon, J. A., & Eichhorn, P. J. A. (2021) · Cancers · doi:10.3390/cancers13071538 · Cited by 110 · see citing works
“There are currently two types of inhibitors in this category: allosteric mTORC1 inhibitors or the ATP‐competitive catalytic mTOR inhibitors [59].”
Background
Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity
Faes, S., Demartines, N., & Dormond, O. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1726078 · Cited by 104 · see citing works
“By now, three generations of mTORC1 inhibitors have been developed [26].”
Background
The 3.2-Å resolution structure of human mTORC2
Scaiola, A., Mangia, F., Imseng, S., Boehringer, D., Berneiser, K., Shimobayashi, M., Stuttfeld, E., Hall, M. N., Ban, N., & Maier, T. (2020) · Science Advances · doi:10.1126/sciadv.abc1251 · Cited by 104 · see citing works
“…proliferation ( 4 ) by phosphoryl ating the AGC family kinases: AKT, PKC, and SGK ( 1 , 4 , 11 – 13 ). mTORC2 also promotes tumorigenesis via up-regulation of lipid biosynthesis ( 14 ). mTOR inhibitors played a major role in the elucidation of mTOR signaling and are used in cancer treatment ( 15 ).”
Medication-related osteonecrosis of the jaw unrelated to bisphosphonates and denosumab—a review
King, R., Tanna, N., & Patel, V. (2018) · Oral Surgery Oral Medicine Oral Pathology and Oral Radiology · doi:10.1016/j.oooo.2018.11.012 · Cited by 102 · see citing works
Tumor reactive stroma in cholangiocarcinoma: The fuel behind cancer aggressiveness
Brivio, S., Cadamuro, M., Strazzabosco, M., & Fabris, L. (2017) · World Journal of Hepatology · doi:10.4254/wjh.v9.i9.455 · Cited by 96 · see citing works
Transcription and Translation Inhibitors in Cancer Treatment
Laham-Karam, N., Pinto, G., Poso, A., & Kokkonen, P. (2020) · Frontiers in Chemistry · doi:10.3389/fchem.2020.00276 · Cited by 88 · see citing works
“However, since mTOR signaling is essential for cell viability, blocking both mTOR complexes causes mTOR kinase inhibitors to have more severe side effects than rapamycin or rapalogs (Xie et al., 2016).”
Background
Understanding Breast cancer: from conventional therapies to repurposed drugs
Costa, B., Amorim, I., Gärtner, F., & Vale, N. (2020) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2020.105401 · Cited by 93 · see citing works
Controversies around the function of LARP1
Berman, A. J., Thoreen, C. C., Dedeić, Z., Chettle, J., Roux, P. P., & Blagden, S. P. (2020) · RNA Biology · doi:10.1080/15476286.2020.1733787 · Cited by 79 · see citing works
The mixed blessing of AMPK signaling in Cancer treatments
Sadria, M., Seo, D., & Layton, A. T. (2022) · BMC Cancer · doi:10.1186/s12885-022-09211-1 · Cited by 80 · see citing works
Targeting the Lysosome for Cancer Therapy
Towers, C. G., & Thorburn, A. M. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0996 · Cited by 79 · see citing works
Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development
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Evolving Significance and Future Relevance of Anti-Angiogenic Activity of mTOR Inhibitors in Cancer Therapy
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mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)
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Authors: Xie, J., Wang, X., & Proud, C. G.
Affiliations: South Australian Health and Medical Research Institute (AU)
Corresponding author: Proud, Christopher G.
ORCID: Xie, Jianling
Wang, Xuemin
Proud, Christopher G.
Venue: F1000Research
Publisher: F1000 Research Ltd
Published: 2016-08-25
Volume: 5
Pages: 2078
ISSN: 2046-1402 (ISSN-L)
DOI: 10.12688/f1000research.9207.1
PMC: PMC5007757
OpenAlex: W2517175971
Cited by: 266
References: 84
Citations by year: 2026: 8 · 2025: 14 · 2024: 9 · 2023: 21 · 2022: 31 · 2021: 36 · 2020: 49 · 2019: 32 · 2018: 37 · 2017: 28 · 2016: 1
FWCI: 2.96
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: F1000Research (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: mTOR inhibitors, mammalian target of rapamycin, mTORC1, mTORC2, rapamycin, cancer therapy, cell growth and proliferation, oncogenic signaling, feedback loops, drug resistance

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