4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors
Open accessAbstract
PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.
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Anti-proliferative efficacy requires dephosphorylation of 4E-BP1 and consequent inhibition of cap-dependent translation.
“This is consistent with previous reports and with our previous finding that anti-proliferative efficacy requires dephosphorylation of 4E-BP1 and its consequent inhibition of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The Results sections report that 4E-BP1 dephosphorylation inhibits cap-dependent translation and that a nonphosphorylatable 4E-BP1 mutant suppresses tumor growth in vivo. However, the experiments concern particular tumor models, and reduced 4E-BP1 expression attenuated rather than abolished the response to pathway inhibition; the paper does not establish dephosphorylation as an absolute requirement for anti-proliferative efficacy generally. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCombined inhibition of MEK and AKT attenuates the growth of KRAS tumors, and this effect depends on suppression of 4E-BP1 phosphorylation.
“We have previously shown that combined inhibition of MEK and AKT attenuates the growth of KRAS tumors and that this is dependent on suppression of 4E-BP1 phosphorylation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The Results section on tumor growth in vivo reports that combined MEK and AKT inhibition suppressed growth in four tested models with concurrent KRAS and PIK3CA mutations, while also suppressing 4E-BP1 phosphorylation. The 4E-BP1 experiments support its role in the response, but do not establish that the drug combination’s effect on tumor growth depends on 4E-BP1 dephosphorylation. The claim also broadens the studied population from tumors with both mutations to KRAS tumors generally (page numbers unavailable in our copy). (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation, and both pathways must be inhibited to affect tumor growth or survival.
“We have previously shown that the PI3K/AKT/mTOR and RAS/RAF/ERK pathways converge on key cellular processes, including Cyclin D-Cdk4/6 activation and cap-dependent translation and that both pathways must be inhibited to affect tumor growth or survival15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The Results (page not provided) show that tumors with coexistent pathway activation are sensitive to combined AKT and MEK/ERK inhibition, and that both pathways support cap-dependent translation. The paper also reports effects on cyclin D1 expression, but the passages do not establish Cyclin D–Cdk4/6 activation; its combined-inhibition finding is limited to tumors with coexistent pathway activation, not tumors generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAKT and MEK inhibition cooperate to inhibit 4E-BP1 phosphorylation, and dephosphorylation of 4E-BP1 is required for the anti-tumor activity of the combination.
“We have previously shown that AKT and MEK inhibition cooperate to inhibit 4E-BP1 phosphorylation and that dephosphorylation of 4E-BP1 is required for the anti-tumor activity of the combination15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
The Results section reports that combined AKT and MEK inhibition synergistically reduced 4E-BP1 phosphorylation and suppressed tumor growth in the tested models (page not specified). It also reports that reducing 4E-BP1 expression attenuated the combination’s apoptotic effect and that a nonphosphorylatable 4E-BP1 mutant suppressed tumor growth. Those findings support a role for 4E-BP1 dephosphorylation, but do not establish that it is required for the combination’s anti-tumor activity. (LLM, conf=0.88)
Experimental — accuracy not yet measured4E-BP1 is a convergent target of PI3K/AKT/mTOR and RAF/MEK/ERK pathways and integrates their function at the level of regulation of cap-dependent translation.
“These data are consistent with our previous findings that 4E-BP1 is a convergent target of PI3K/AKT/mTOR and RAF/MEK/ERK pathways and integrates their function at the level of regulation of cap-dependent translation15.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways.
“Nevertheless, these data are consistent with our previous findings that inhibition of the growth of tumors in which ERK and PI3K/mTOR signaling are dysregulated requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
Several downstream processes are under the control of both ERK and PI3K/mTOR signaling and their effective inhibition requires inhibition of both pathways.
“We have previously shown that several downstream processes are under the control of both ERK and PI3K/mTOR signaling and that their effective inhibition requires inhibition of both pathways15,24.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [15]
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BackgroundCorcoran, R. B., Cheng, K. A., Hata, A. N., Faber, A. C., Ebi, H., Coffee, E. M., Greninger, P., Brown, R. D., Godfrey, J. T., Cohoon, T. J., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.007 · Cited by 377 · see citing works
Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells
Muranen, T. E., Selfors, L. M., Worster, D. T., Iwanicki, M., Song, L., Morales, F. C., Gao, S., Mills, G. B., & Brugge, J. S. (2012) · Cancer Cell · doi:10.1016/j.ccr.2011.12.024 · Cited by 385 · see citing works
“…of mTORC1 or perturbation of 4E-BP1 (Braunstein et al., 2007; Choo et al., 2008; Feldman et al., 2009; Hsieh et al., 2010; Moerke et al., 2007; She et al., 2010; Thoreen et al., 2009). mRNAs translated under these conditions have a highly structured 5 0 -untranslated region (5 0 -UTR), which…”
New frontiers in translational control of the cancer genome
Truitt, M. L., & Ruggero, D. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.27 · Cited by 378 · see citing works
Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer
Saini, K. S., Loi, S., de Azambuja, E., Metzger, O., Saini, M. L., Ignatiadis, M., Dancey, J. E., & Piccart, M. J. (2013) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2013.03.009 · Cited by 376 · see citing works
Shuda, M., Kwun, H. J., Feng, H., Chang, Y., & Moore, P. S. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46323 · Cited by 374 · see citing works
Tao, S., Yuan, T., Rui, B., Zhu, Z., Guo, S., & Zhang, C. (2017) · Theranostics · doi:10.7150/thno.17450 · Cited by 347 · see citing works
“Through these two important pathways [60], EC apoptosis was rescued and vascularization was greatly improved, with rapid promotion of the blood supply.”
Background4E-BP1, a multifactor regulated multifunctional protein
Qin, X., Jiang, B., & Zhang, Y. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1151581 · Cited by 338 · see citing works
“ble that other kinases cooperate with or independent of mTORC1 regulate its phosphorylation.(17,18) We have shown”
BackgroundLoss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence
Nissan, M. H., Pratilas, C., Jones, A. M., Ramirez, R., Won, H., Liu, C.-L., Tiwari, S., Kong, L., Hanrahan, A. J., Yao, Z., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2625 · Cited by 297 · see citing works
“Furthermore, co-treatment with PD0325901 and the pan-AKT inhibitor MK2206 did not augment growth inhibition or induce apoptosis as has been shown in colorectal cells with RAS activation (34) (Supplemental Fig.”
Self-citationSingle-cell proteomic chip for profiling intracellular signaling pathways in single tumor cells
Shi, Q., Qin, L., Wei, W., Geng, F., Fan, R., Shin, Y. S., Guo, D., Hood, L., Mischel, P. S., & Heath, J. R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110865109 · Cited by 318 · see citing works
“This preferential activation of MAPK signaling pathways in response to EGF activation in GBM cells containing PTEN was validated by immunoblot analysis (Fig.”
BackgroundInfluentialmTORC1-mediated translational elongation limits intestinal tumour initiation and growth
Faller, W. J., Jackson, T. J., Knight, J. R. P., Ridgway, R. A., Jamieson, T. J., Karim, S. A., Jones, C., Radulescu, S., Huels, D. J., Myant, K., et al. (2014) · Nature · doi:10.1038/nature13896 · Cited by 302 · see citing works
Erratum: New frontiers in translational control of the cancer genome
Truitt, M., & Ruggero, D. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.30 · Cited by 306 · see citing works
The plasticity of mRNA translation during cancer progression and therapy resistance
Fabbri, L., Chakraborty, A., Robert, C., & Vagner, S. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00380-y · Cited by 273 · see citing works
Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy
Steelman, L. S., Franklin, R. A., Abrams, S. L., Chappell, W. H., Kempf, C., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., Nicoletti, F., et al. (2011) · Leukemia · doi:10.1038/leu.2011.66 · Cited by 261 · see citing works
Mutant BRAF Melanomas—Dependence and Resistance
Poulikakos, P. I., & Rosen, N. X. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.008 · Cited by 250 · see citing works
Self-citationHoeflich, K. P., Merchant, M., Orr, C., Chan, J., Den Otter, D., Berry, L., Kasman, I., Koeppen, H., Rice, K., Yang, N.-Y., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1515 · Cited by 242 · see citing works
Negative Feedback and Adaptive Resistance to the Targeted Therapy of Cancer
Chandarlapaty, S. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0018 · Cited by 235 · see citing works
“For instance, in tumors with RAS and PIK3CA mutations, downregulation of both AKT and ERK is necessary to fully recruit the 4EBP1 suppressor to the eIF4E mRNA cap complex to block cap-dependent translation (25).”
Posch, C., Moslehi, H., Feeney, L., Green, G. A., Ebaee, A., Feichtenschlager, V., Kim, C. A., Peng, L. W. T., Dimon, M. T., Phillips, T., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216013110 · Cited by 234 · see citing works
Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway
Atefi, M. S., von Euw, E., Attar, N., Ng, C., Chu, C., Guo, D., Nazarian, R., Chmielowski, B., Glaspy, J. A., Comin-Anduix, B., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028973 · Cited by 230 · see citing works
“The concept of simultaneous inhibition of the MAPK and the PI3K/AKT/ mTOR pathways has been widely considered to treat altered oncogenic signals [7,18,20,26], and at least one clinical trial combining a MEK inhibitor with an AKT inhibitor is currently underway (NCT01021748).”
BackgroundMaximising the potential of AKT inhibitors as anti-cancer treatments
Brown, J. S., & Banerji, U. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.12.001 · Cited by 222 · see citing works
“There are now several lines of evidence showing that tumours harbouring activatingmutations in both the PI3K/AKTandMAPK signalling networks, require inhibition of both to negatively affect tumour growth and survival, due to significant crosstalk and redundancy between the pathways (Davies et al., 2012; She et al., 201…”
BackgroundShi, H., Kong, X., Ribas, A., & Lo, R. S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0140 · Cited by 222 · see citing works
Ebi, H., Corcoran, R. B., Singh, A., Chen, Z., Song, Y., Lifshits, E., Ryan, D. P., Meyerhardt, J. A., Benes, C., Settleman, J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57909 · Cited by 210 · see citing works
Chen, J., Li, K., Chen, J., Wang, X., Ling, R., Cheng, M., Chen, Z., Chen, F., He, Q., Li, S., et al. (2022) · 癌症：英文版 · doi:10.1002/cac2.12273 · Cited by 202 · see citing works
“Interestingly, the PI3K/AKT/mTOR signaling pathway has also been shown to play a pivotal role inmRNA translation through ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP1) [48, 49].”
BackgroundWill, M., Qin, A. C. R., Toy, W., Yao, Z., Rodrik-Outmezguine, V. S., Schneider, C., Huang, X., Monian, P., Jiang, X., de Stanchina, E., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0611 · Cited by 195 · see citing works
Self-citationShowkat, M., Beigh, M. A., & Andrabi, K. I. (2014) · Molecular Biology International · doi:10.1155/2014/686984 · Cited by 191 · see citing works
“Dysregulated expression as well as increased phosphorylation of 4E-BPs in cancer also results in poor patient prognosis and the loss of 4EBP1 with the resulting activation of cap dependent translation promotes cell-cycle progression and cell proliferation in culture [136, 137] whereas overexpression of constitutively…”
BackgroundSurvival of pancreatic cancer cells lacking KRAS function
Muzumdar, M. D., Chen, P.-Y., Dorans, K. J., Chung, K. M., Bhutkar, A., Hong, E., Noll, E. M., Sprick, M. R., Trumpp, A., & Jacks, T. (2017) · Nature Communications · doi:10.1038/s41467-017-00942-5 · Cited by 177 · see citing works
Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance
Castellano, E., Sheridan, C., Thin, M. Z., Nye, E. L., Spencer‐Dene, B., Diefenbacher, M. E., Moore, C., Kumar, M. S., Murillo, M. M., Gronroos, E. C., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.012 · Cited by 184 · see citing works
Mitogen-activated protein kinases in hepatocellular carcinoma development
Min, L., He, B., & Hui, L. (2010) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2010.10.011 · Cited by 176 · see citing works
Ribosome biogenesis: An emerging druggable pathway for cancer therapeutics
Catez, F., Venezia, N. D., Marcel, V., Zorbas, C., Lafontaine, D. L. J., & Diaz, J. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.014 · Cited by 175 · see citing works
McCubrey, J. A., Steelman, L. S., Kempf, C., Chappell, W. H., Abrams, S. L., Stivala, F., Malaponte, G., Nicoletti, F., Libra, M., Bäsecke, J., et al. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22647 · Cited by 173 · see citing works
“Kinase Inhibitors It has been known for quite some time now, that treatmentwith certain inhibitors (e.g., Raf inhibitors), can result in hyperactivation of WT Raf (Hall-Jackson et al., 1999; Lee and McCubrey, 2002a; Lee and McCubrey, 2002b; Chang et al., 2003; Shelton et al., 2003).”
BackgroundHalilovic, E., She, Q.-B., Ye, Q., Pagliarini, R., Sellers, W. R., Solit, D. B., & Rosen, N. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0409 · Cited by 168 · see citing works
Self-citationMechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia
Chen, L. S., Redkar, S., Taverna, P., Cortes, J. E., & Gandhi, V. V. (2011) · Blood · doi:10.1182/blood-2010-12-323022 · Cited by 169 · see citing works
NRAS mutant melanoma: biological behavior and future strategies for therapeutic management
Fedorenko, I. V., Gibney, G. T., & Smalley, K. S. M. (2012) · Oncogene · doi:10.1038/onc.2012.453 · Cited by 168 · see citing works
mTOR signaling in tumorigenesis
Xu, K. L., Liu, P., & Wei, W. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.10.007 · Cited by 167 · see citing works
Ye, Q., Cai, W., Zheng, Y., Evers, B. M., & She, Q. (2013) · Oncogene · doi:10.1038/onc.2013.122 · Cited by 162 · see citing works
Self-citationIGFBP7 Binds to the IGF-1 Receptor and Blocks Its Activation by Insulin-Like Growth Factors
Evdokimova, V., Tognon, C. E., Benatar, T., Yang, W., Krutikov, K., Pollak, M., Sorensen, P. H. B., & Seth, A. (2012) · Science Signaling · doi:10.1126/scisignal.2003184 · Cited by 176 · see citing works
KRAS and BRAF: drug targets and predictive biomarkers
Vakiani, E., & Solit, D. B. (2010) · The Journal of Pathology · doi:10.1002/path.2796 · Cited by 158 · see citing works
Self-citationMutant KRAS Conversion of Conventional T Cells into Regulatory T Cells
Zdanov, S., Mandapathil, M., Eid, R. A., Adamson-Fadeyi, S., Wilson, W., Qian, J., Carnie, A., Tarasova, N. I., Mkrtichyan, M., Berzofsky, J. A., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0241 · Cited by 157 · see citing works
“This is thought to be due to the interaction between the MEK–ERK and PI3K–Akt pathways (42, 43).”
BackgroundeIF4E/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 · see citing works
“Recent studies have proposed that the combination of mitogen-activated protein kinase with mTOR inhibitors could overcome resistance to mTOR inhibitors (42, 45).”
BackgroundThe evolution of the TOR pathway and its role in cancer
Beauchamp, E. M., & Platanias, L. C. (2012) · Oncogene · doi:10.1038/onc.2012.567 · Cited by 153 · see citing works
Tan, J. Y., Li, Z., Lee, P. L., Guan, P., Aau, M. Y., Lee, S. T., Feng, M., Lim, C. Z., Lee, E. Y. J., Wee, Z. N., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0595 · Cited by 150 · see citing works
The biological and therapeutic relevance of mRNA translation in cancer
Blagden, S. P., & Willis, A. E. (2011) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2011.16 · Cited by 149 · see citing works
“Studies of β-adrenergic signaling cascades in mouse hippocampal tissue indicate that both mTOR and MAPK pathways must be concurrently active in order for translation to occur”
BackgroundKhalili, J. S., Yu, X., Wang, J., Hayes, B. C., Davies, M. A., Lizee, G. A., Esmaeli, B., & Woodman, S. E. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-3227 · Cited by 147 · see citing works
“, colon carcinomas with both KRAS and PI3KCA mutations)(27).”
Morkel, M., Riemer, P., Bläker, H., & Sers, C. (2015) · Oncotarget · doi:10.18632/oncotarget.4750 · Cited by 143 · see citing works
“In this regard, it is important that the PIK3CA-AKT-mTOR axis is frequently activated either by loss of PTEN or activation of PIK3CA in CRC, independent of the KRAS or BRAF status [132].”
BackgroundInfluentialAkhavan, D., Pourzia, A. L., Nourian, A. A., Williams, K. J., Nathanson, D. A., Babić, I., Villa, G. R., Tanaka, K., Nael, A., Yang, H., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0502 · Cited by 141 · see citing works
“a parallel pathway (38) by which ERK signaling also suppresses PDGFRβ.”
Antitumor Activity in RAS -Driven Tumors by Blocking AKT and MEK
Tolcher, A. W., Khan, K. H., Ong, M., Banerji, U., Papadimitrakopoulou, V. A., Gandara, D. R., Patnaik, A., Baird, R. D., Olmos, D., Garrett, C. R., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1901 · Cited by 137 · see citing works
“Numerous preclinical models have suggested that KRASmutant tumors require cotargeting of the Ras/Raf/MEK/ERK and PI3K/AKT pathways due to multiple points of cross-talk, negative feedback, and redundancy (6, 7).”
BackgroundRegulation of PTEN translation by PI3K signaling maintains pathway homeostasis
Mukherjee, R., Vanaja, K. G., Boyer, J. A., Gadal, S., Solomon, H., Chandarlapaty, S., Levchenko, A., & Rosen, N. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.033 · Cited by 135 · see citing works
“This mutant is unphosphorylatable and binds constitutively to eIF4E causing inhibition of cap-dependent translation (Cai et al., 2014; She et al., 2010).”
BackgroundSelf-citationInhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours
Wu, Z. R., Yan, L., Liu, Y. T., Cao, L., Guo, Y., Zhang, Y., Yao, H., Cai, L., Shang, H. B., Rui, W. W., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06853-3 · Cited by 135 · see citing works
mTORC1 is essential for leukemia propagation but not stem cell self-renewal.
Hoshii, T., Tadokoro, Y., Naka, K., Ooshio, T., Muraguchi, T., Sugiyama, N., Soga, T., Araki, K., Yamamura, K., & Hirao, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62279 · Cited by 128 · see citing works
“Although previous studies reported that inhibition of 4E-BP phosphorylation is associated with the induction of apoptosis in tumors (39, 40), it was assumed that other molecules downstream of mTORC1 cooperatively contribute to AML propagation.”
ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
Winter, J. N., Jefferson, L. S., & Kimball, S. R. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00504.2010 · Cited by 130 · see citing works
“A recent study (44) demonstrated that in tumor cell lines in which independent mutations occur in both the catalytic subunit of phosphoinositide-3 kinase (PI3K) and B-Raf, inhibition of either the Akt or ERK pathway alone is ineffective in repressing cell proliferation.”
BackgroundS6K1 Alternative Splicing Modulates Its Oncogenic Activity and Regulates mTORC1
Ben-Hur, V., Denichenko, P., Siegfried, Z., Maimon, A., Krainer, A. R., Davidson, B., & Karni, R. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.020 · Cited by 129 · see citing works
“We next examined, using two complementary strategies, if this activation is required for their oncogenic activities: 1) Inhibition of mTORC1 by the pharmacological inhibitor rapamycin and 2) expression of a phosphorylation-defective 4E-BP1 which is mutated in its phosphorylation sites and cannot dissociate from eIF4E…”
BackgroundMethodInfluentialCDK1 substitutes for mTOR kinase to activate mitotic cap-dependent protein translation
Shuda, M., Velásquez, C., Cheng, E., Cordek, D. G., Kwun, H. J., Chang, Y., & Moore, P. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1505787112 · Cited by 127 · see citing works
“Mounting evidence suggests that dysregulated cap-dependent translation from aberrant PI3K–Akt–mTOR and MEF–RAF–MEK–ERK signaling contributes to cancer cell transformation (3, 52).”
BackgroundAkt: a key transducer in cancer
Tsai, P., Lai, Y., Manne, R., Tsai, Y.-S., Sarbassov, D. D., & Lin, H. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00860-9 · Cited by 130 · see citing works
“Similarly, overexpression of mutant 4E-BP1 inhibits PI3KCA and K-Ras mutant tumor growth in the xenograft tumor model [81].”
BackgroundCYP1A1 Regulates Breast Cancer Proliferation and Survival
Rodriguez, M., & Potter, D. A. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0675 · Cited by 124 · see citing works
“These reductions in phosphorylation correlate with downstream inhibition of the protein synthesis regulator P70S6K (23, 24).”
BackgroundInfluentialThe nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53
Lee, S.-O., Andey, T. A., Jin, U.-H., Kim, K., Sachdeva, M. S., & Safe, S. H. (2011) · Oncogene · doi:10.1038/onc.2011.504 · Cited by 122 · see citing works
“The phosphorylated forms of 4E-BP1 and p70S6K are key downstream targets of mTORC1 that regulate initiation and translation of multiple genes, such as cyclin D1 and cyclin A, that are critical for normal cell growth, and in a cancer context many of the the 4E-BP1- and p70S6K-regulated genes are prooncogenic (Hay and S…”
Hernandez, B., Adissu, H. A., Wei, B., Michael, H., Merlino, G. T., & Simpson, R. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020394 · Cited by 121 · see citing works
“Inhibition of both pathways may be beneficial due to significant crosstalk and redundancy between the pathways [8,80].”
BackgroundCurrent State and Future Challenges for PI3K Inhibitors in Cancer Therapy
Sirico, M., D’Angelo, A., Gianni, C., Casadei, C., Merloni, F., & De Giorgi, U. (2023) · Cancers · doi:10.3390/cancers15030703 · Cited by 121 · see citing works
“It can potentially treat a wide range of solid and hematologic malignancies as a monotherapy or in combination, both in vivo and in vitro [86].”
BackgroundFaber, A. C., Coffee, E. M., Costa, C., Dastur, A., Ebi, H., Hata, A. N., Yeo, A. T., Edelman, E. J., Song, Y., Tam, A. T., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0315 · Cited by 124 · see citing works
Yellen, P., Saqcena, M., Salloum, D., Feng, J., Preda, A., Xu, L., Rodrik-Outmezguine, V. S., & Foster, D. A. (2011) · Cell Cycle · doi:10.4161/cc.10.22.18124 · Cited by 117 · see citing works
Signaling cross-talk in the resistance to HER family receptor targeted therapy
Yamaguchi, H., Chang, S. H., Hsu, J. L., & Hung, M. (2013) · Oncogene · doi:10.1038/onc.2013.74 · Cited by 115 · see citing works
Genomic Complexity and AKT Dependence in Serous Ovarian Cancer
Hanrahan, A. J., Schultz, N. D., Westfal, M. L., Sakr, R. A., Giri, D. D., Scarperi, S., Janikariman, M., Olvera, N., Stevens, E. V., She, Q., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0170 · Cited by 114 · see citing works
Self-citationAmino acid management in cancer
Tsun, Z.-Y., & Possemato, R. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.08.002 · Cited by 113 · see citing works
Anti-oncogenic potential of the eIF4E-binding proteins
Martineau, Y., Azar, R., Bousquet, C., & Pyronnet, S. (2012) · Oncogene · doi:10.1038/onc.2012.116 · Cited by 112 · see citing works
Zhang, X., Hua, R., Wang, X., Huang, M., Gan, L., Wu, Z., Zhang, J., Wang, H., Cheng, Y., Li, J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.6890 · Cited by 109 · see citing works
“Furthermore, the expression of p-ERK and p-AKT, which have been reported to effect tumorigenesis in tandem [40, 41] were both highly expressed together in gastric CSCs isolated in this study.”
BackgroundMissailidis, D., Annesley, S. J., Allan, C. Y., Sanislav, O., Lidbury, B. A., Lewis, D. P., & Fisher, P. R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031074 · Cited by 107 · see citing works
“Together with S6 kinase (S6K), 4E-BP1 mediates the roles of TORC1 in regulating translation in the cytosol of mRNAs encoding major functional groups of proteins [40-42].”
BackgroundSee, W. L., Tan, I., Mukherjee, J., Nicolaides, T. P., & Pieper, R. O. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0334 · Cited by 106 · see citing works
“Alternatively, MEK inhibitor– based trials could be designed to include a PI3K/mTOR inhibitor, addition of which enhances MEK inhibitor sensitivity (13, 14, 16, 36, 38, 39), and may target a broader GBM population.”
BackgroundActivating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis
Charles, R., Silva, J. M., Iezza, G., Phillips, W. A., & McMahon, M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0158-t · Cited by 104 · see citing works
“on the phosphorylation of ribosomal protein S6 (rpS6) and 4E-BP1, that latter of which directly regulates Cap-dependent protein translation [17].”
BackgroundEffect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor
Kalinsky, K. M., Hong, F., McCourt, C. K., Sachdev, J. C., Mitchell, E. P., Zwiebel, J. A., Doyle, L. A., McShane, L. M., Li, S., Gray, R. J., et al. (2020) · JAMA Oncology · doi:10.1001/jamaoncol.2020.6741 · Cited by 102 · see citing works
Targeting mTOR network in colorectal cancer therapy
Wang, X. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i15.4178 · Cited by 100 · see citing works
S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer
Nawroth, R., Stellwagen, F., Schulz, W. A., Stoehr, R., Hartmann, A., Krause, B. J., Gschwend, J. E., & Retz, M. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027509 · Cited by 97 · see citing works
“events of the PI3K and MAPK pathway in tumors [15].”
BackgroundInfluentialTanaka, H., Yoshida, M., Tanimura, H., Fujii, T., Sakata, K., Tachibana, Y., Ohwada, J., Ebiike, H., Kuramoto, S., Morita, K., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2882 · Cited by 97 · see citing works
Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer
Donnella, H. J., Webber, J. T., Levin, R. S., Camarda, R., Momcilovic, O., Bayani, N., Shah, K. N., Korkola, J. E., Shokat, K. M., Goga, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0081-9 · Cited by 90 · see citing works
“This may be due to the convergence of both the PI3K and MAPK pathways on protein synthesis 38,39 .”
Sun, H., Yang, W., Tian, Y., Zeng, X., Zhou, J., Mok, M. T. S., Tang, W., Feng, Y., Xu, L., Chan, A. W. H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07402-8 · Cited by 93 · see citing works
He, K., Zheng, X., Li, M., Zhang, L., & Yu, J. (2015) · Oncogene · doi:10.1038/onc.2015.79 · Cited by 92 · see citing works
“S3C-D), supporting mTOR-independent 4E-BP1 phosphorylation in CRC cells (22).”
mRNA Translation and Energy Metabolism in Cancer: The Role of the MAPK and mTORC1 PathwaysPreprint
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“Accordingly, combined inhibition of MAPK and PI3K/AKT completely and sustainably inhibits the phosphorylation of 4E-BPs, which is paralleled by tumor growth reduction (She et al. 2010).”
BackgroundDucker, G. S., Atreya, C. E., Simko, J. P., Hom, Y. K., Matli, M. R., Benes, C. H., Hann, B. C., Nakakura, E. K., Bergsland, E. K., Donner, D. B., et al. (2013) · Oncogene · doi:10.1038/onc.2013.92 · Cited by 89 · see citing works
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“4E-BP1 was demonstrated to be an essential factor that transduces oncogenic signals downstream of the AKTmTOR and ERK pathways (55, 56).”
BackgroundMYC Cooperates with AKT in Prostate Tumorigenesis and Alters Sensitivity to mTOR Inhibitors
Clegg, N. J., Couto, S. S., Wongvipat, J., Hieronymus, H., Carver, B. S., Taylor, B. S., Ellwood‐Yen, K., Gerald, W. L., Sander, C., & Sawyers, C. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017449 · Cited by 89 · see citing works
“Furthermore, phosphorylation of 4EBP1 was unimpaired by mTOR inhibition in these mice (but rather increased, possibly due to feedback activation of the MEK/ERK-pathway [44]).”
BackgroundSynthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors
Liu, T., Nair, S. J., Lescarbeau, A., Belani, J. D., Peluso, S., Conley, J., Tillotson, B. P., O’Hearn, P. J., Smith, S. A., Slocum, K. L., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3011542 · Cited by 86 · see citing works
Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer
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“The mechanisms reported to underlie this synergy include downstream convergence of translational control of prosurvival signaling (29) and modulation of expression of proapoptotic and antiapoptotic BH3 proteins (30).”
BackgroundDNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR
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“Modulation of PI3K and downstream signaling effectors including AKT, mTORC1, and/or mTORC2 can have marked effects on melanoma formation (Damsky et al., 2015; Damsky et al., 2011; Karbowniczek et al., 2008; She et al., 2010).”
Background
- Authors
- She, Q.-B., Halilovic, E., Ye, Q., Zhen, W., Shirasawa, S., Sasazuki, T., Solit, D. B., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Fukuoka University (JP)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 18
- Issue
- 1
- Pages
- 39-51
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3286650
- OpenAlex
- W2084875329
- Cited by
- 400
- References
- 50
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 16 · 2023: 12 · 2022: 21 · 2021: 17 · 2020: 11 · 2019: 16 · 2018: 23 · 2017: 26 · 2016: 22 · 2015: 33 · 2014: 45 · 2013: 42 · 2012: 49
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA129243, P01CA094060)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- 4E-BP1, Akt signaling, ERK signaling, PIK3CA mutation, PTEN loss, cap-dependent translation, translational repressor, MEK inhibitors, AKT inhibitors, combination therapy synergy, oncogene activation
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Colonic Neoplasms, Female, Humans, Mice, Nude, Mutation, Phosphoproteins, RNA, Messenger, Protein Biosynthesis, Tumor Cells, Cultured, Blotting, Western, Signal Transduction, Survival Rate, Apoptosis, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, Adaptor Proteins, Signal Transducing, Cell Proliferation, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, Class I Phosphatidylinositol 3-Kinases
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