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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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“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]
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“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]
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“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]
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In the citing paper
“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]
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“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]
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“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]
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“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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“This finding is consistent with a report suggesting that other KRAS-regulated pathways, in addition to MEK-ERK, contribute to phosphorylation of 4EBP1(45).”
From mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1 (2014) · cites this paper as [45]
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Citations
Cites
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Cited by
Sorted by citations
Items 101–200 of 401
Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth
Lee, B. J., Boyer, J. A., Burnett, G. L., Thottumkara, A. P., Tibrewal, N., Wilson, S. L., Hsieh, T., Marquez, A., Lorenzana, E. G., Evans, J., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00813-7 · Cited by 87
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“Moreover, 4EBP1/eIF4E has been found to be a major effector of the oncogenic activation of AKT- and ERK-signaling pathways in tumor cell lines and xenograft models.(20)”
BackgroundLittlepage, L. E., Adler, A. S., Kouros‐Mehr, H., Huang, G., Chou, J., Krig, S. R., Griffith, O. L., Korkola, J. E., Qu, K., Lawson, D. A., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0093 · Cited by 88
“Combinatorial pathway activation may be therapeutically important in treating patients with high ZNF217 expression, as concurrent activation of the PI3K/AKT and RAS/MAPK pathways causes resistance to AKT inhibition in cells (33).”
4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer
Wang, Z., Feng, X., Molinolo, A., Martı́n, D., Vitale-Cross, L. A., Nohata, N., Ando, M., Wahba, A., Amornphimoltham, P., Wu, X., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-1220 · Cited by 84
“A phosphorylation-defective mutant of 4E-BP1 (T37A, T46A, S65A, and T70A, 4E-BP1 M) was engineered using appropriate oligonucleotides and the QuikChange II method, and cloned into a tetracycline-inducible lentiviral vector tagged with GFP (pLTI-GFP-4E-BP1 mut)(21,22).”
MethodDirect Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells
Soifer, H. S., Souleimanian, N. E., Wu, S., Voskresenskiy, A. M., Collak, F. K., Cinar, B., & Stein, C. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.261933 · Cited by 81
“Our observation that phospho-4EBP1 levels are significantly reduced after treatment with these both TOK001 and, to a lesser extent, abiraterone alcohol suggests amechanism by which cap-dependent translation is suppressed by blocking assembly of the eIF4F complex to the mRNA 5 cap (54).”
BackgroundImpact of Combined mTOR and MEK Inhibition in Uveal Melanoma Is Driven by Tumor Genotype
Ho, A. L., Musi, E., Ambrosini, G., Nair, J. S., Vasudeva, S. D., de Stanchina, E., & Schwartz, G. K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040439 · Cited by 83
“BRAF and RAS mutations mediate resistance to AKT targeted agents [23].”
BackgroundInfluentialSigma1 Pharmacology in the Context of Cancer
Kim, F. J., & Maher, C. M. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_38 · Cited by 81
mTOR Signaling Confers Resistance to Targeted Cancer Drugs
Guri, Y., & Hall, M. N. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.10.006 · Cited by 81
Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation
Cope, C. L., Gilley, R., Balmanno, K., Sale, M. J., Howarth, K., Hampson, M., Smith, P. D., Guichard, S. M., & Cook, S. J. (2013) · Journal of Cell Science · doi:10.1242/jcs.137588 · Cited by 82
“contrast, S6K makes a more modest contribution to the oncogenic action of ERK1/2 or PKB compared to the 4EBP–eIF4E pathway (Hsieh et al., 2010; She et al., 2010).”
BackgroundMiddleton, G., Crack, L. R., Popat, S., Swanton, C., Hollingsworth, S. J., Buller, R., Walker, I., Carr, T. H., Wherton, D., & Billingham, L. J. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv394 · Cited by 78
“There is collaborative inactivation of the translational repressor 4E-BP1 by both AKT and ERK signalling [11], ERK directly inactivates TSC2 by phosphorylation [12].”
BackgroundShoji, K., Oda, K., Kashiyama, T., Ikeda, Y., Nakagawa, S., Sone, K., Miyamoto, Y., Hiraike, H., Tanikawa, M., Miyasaka, A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037431 · Cited by 78
“were resistant to AKT inhibitors, and suggested that a MEK inhibitor sensitizes these double mutant cells to AKT or PI3K inhibitors”
BackgroundOncogenic AKTivation of translation as a therapeutic target
Hsieh, A. C., Truitt, M., & Ruggero, D. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.241 · Cited by 79
“Importantly, the authors were able to attribute this combinatorial drug effect directly to the inhibition of eIF4E hyperactivity, as the overexpression of a non-phosphorylatable form of 4EBP1 was sufficient to block the growth of these cells in xenografts (She et al, 2010).”
BackgroundCancer’s Achilles’ Heel: Apoptosis and Necroptosis to the Rescue
Dasgupta, A., Nomura, M., Shuck, R. L., & Yustein, J. T. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms18010023 · Cited by 78
Receptor tyrosine kinases and their activation in melanoma
Easty, D. J., Gray, S. G., O'Byrne, K. J., O’Donnell, D., & Bennett, D. C. (2011) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2011.00836.x · Cited by 79
“Interestingly, the translational regulator and tumour suppressor 4E-BP1 was recently reported to be a common target of AKT and MEK signalling, and a potential therapeutic target for cancers with activation of both these pathways (She et al., 2010) (Figure 1).”
BackgroundMizutani, R., Imamachi, N., Suzuki, Y., Yoshida, H., Tochigi, N., Oonishi, T., Suzuki, Y., & Akimitsu, N. (2015) · Oncogene · doi:10.1038/onc.2015.410 · Cited by 76
Activation of Akt/mTOR Pathway Is Associated with Poor Prognosis of Nasopharyngeal Carcinoma
Wang, W., Wen, Q., Xu, L., Xie, G., Li, J., Luo, J., Chu, S., Shi, L., Huang, D., Li, J., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106098 · Cited by 76
“Akt is an important kinase of Akt/mTOR signaling pathway which could phosphorylate the p70S6K and 4EBP1, and both of p70S6K and 4EBP1 are major downstream targets of Akt/mTOR signaling pathway which could regulate protein synthesis and cell cycle progression [14–17].”
BackgroundWang, H., Daouti, S., Li, W., Yang, W., Rizzo, C., Higgins, B., Packman, K. E., Rosen, N. X., Boylan, J. F., Heimbrook, D. C., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4351 · Cited by 76
“Combination targeting of Raf/MEK/ERK and PI3K/AKT/mTOR pathways has been reported in many preclinical models (36, 37).”
BackgroundSelf-citationHata, A. N., Yeo, A., Faber, A. C., Lifshits, E., Chen, Z., Cheng, K. A., Walton, Z., Sarosiek, K. A., Letai, A., Heist, R. S., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3728 · Cited by 74
Fisher, R. A., Horswell, S. D., Rowan, A., Salm, M. P., de Bruin, E. C., Gulati, S., McGranahan, N., Stares, M., Gerlinger, M., Varela, I., et al. (2014) · Genome biology · doi:10.1186/s13059-014-0433-z · Cited by 77
“In tumors without mutations in genes known to impact upon PI3K pathway signaling, we propose that alternative and as yet unknown mechanisms cause pathway activation based on substantial evidence for the integration of multiple regulatory inputs [31] and complex layers of control of the TORC1 complex, including the inf…”
BackgroundQi, L., & Zhang, Y. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000358624 · Cited by 71
Mohan, S., Broek, R. V., Shah, S., Eytan, D. F., Pierce, M., Carlson, S. G., Coupar, J. F., Zhang, J., Cheng, H. W., Chen, Z., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3377 · Cited by 71
“Thus MEK/ERK co-activation may enhance activation of mTOR and its downstream effectors, ribosomal protein S6 and translation repressor 4E-BP1, to integrate the function of ERK and Akt/mTOR signaling in transcription and translation in tumors (38).”
MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas
Grzmil, M., Huber, R. M., Heß, D., Frank, S., Hynx, D., Moncayo, G. E., Klein, D., Merlo, A., & Hemmings, B. A. (2014) · Journal of Clinical Investigation · doi:10.1172/jci70198 · Cited by 71
“Similarly, recent studies in human breast cancer and colorectal cells with PIK3CA and KRAS mutations identified 4EBP1 as a key integrator of the activated PI3K/AKT and ERK pathways (31).”
WU, R. T., Hu, T. C., Rehemtulla, A., Fearon, E. R., & Cho, K. R. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1388 · Cited by 67
“Levels of p4E-BP1 were largely unchanged by rapamycin treatment, in keeping with recent reports that combined inhibition of Akt and Erk signaling is required to suppress 4E-BP1 phosphorylation (24).”
Song, K.-A., Hosono, Y., Turner, C., Jacob, S., Lochmann, T. L., Murakami, Y., Patel, N. U., Ham, J., Hu, B., Powell, K. M., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0304 · Cited by 67
“org Clin Cancer Res; 24(22) November 15, 2018 5661”
BackgroundInfluentialHan, K., Xu, X., Chen, G., Zeng, Y., Zhu, J., Du, X., Zhang, Z., Cao, B., Liu, Z., & Mao, X. (2014) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-7-9 · Cited by 65
“Both p70S6K and 4E-BP1 phosphorylation are regulated by the PI3K/AKT signaling [39,40].”
BackgroundEukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer
Rutkovsky, A. C., Yeh, E. S., Guest, S. T., Findlay, V. J., Muise‐Helmericks, R. C., Armeson, K. E., & Ethier, S. P. (2019) · BMC Cancer · doi:10.1186/s12885-019-5667-4 · Cited by 65
“Because 4EBP1 is required for coupling mTORC1 signaling to Cyclin D1 expression [101] and translational inhibition can result in the loss of cell cycle regulators like the D-cyclins [105], we plan to determine the predictive value of 4EBP1 levels to CDK inhibition in breast tumors, especially in the context of dual in…”
BackgroundRocca, A., Braga, L., Volpe, M. C., Maiocchi, S., & Generali, D. (2022) · Cancers · doi:10.3390/cancers14215306 · Cited by 71
RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth
Roméo, Y., Moreau, J., Zindy, P.-J., Saba-El-Leil, M. K., Lavoie, G., Dandachi, F., Baptissart, M., Borden, K. L. B., Meloche, S., & Roux, P. P. (2012) · Oncogene · doi:10.1038/onc.2012.312 · Cited by 69
Velásquez, C., Cheng, E., Shuda, M., Lee-Oesterreich, P. J., von Strandmann, L. P., Gritsenko, M. A., Jacobs, J., Moore, P. S., & Chang, Y. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607768113 · Cited by 66
“Overexpression of constitutively active 4E-BP1 or 4E-BP2 antagonizes cell transformation induced by eIF4E, v-Src, H-Ras, and MCV sT, indicating that 4E-BP1 acts as a tumor suppressor (41, 44, 45).”
BackgroundWu, L. Y., Maachani, U. B., Schweitzer, M. E., Singh, R., Wang, M., Chang, R. Y., & Souweidane, M. M. (2017) · Translational Oncology · doi:10.1016/j.tranon.2016.12.008 · Cited by 63
Politz, O., Siegel, F., Bärfacker, L., Bömer, U., Hägebarth, A., Scott, W. J., Michels, M., Ince, S. J., Neuhaus, R., Meyer, K., et al. (2016) · International Journal of Cancer · doi:10.1002/ijc.30457 · Cited by 61
Workman, P., Al‐Lazikani, B., & Clarke, P. A. (2013) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2013.06.004 · Cited by 60
Mi, W., Ye, Q., Liu, S., & She, Q. (2015) · Oncotarget · doi:10.18632/oncotarget.3920 · Cited by 61
“We and others have previously shown that the phosphorylation status of 4E-BP1 and its regulated capdependent translation activity are linked with cancer progression and therapeutic responses in tumors such as in breast and colon cancers with mutational activation of the PI3K/AKT signaling pathway [9-13, 26-29].”
InfluentialSelf-citationKorkolopoulou, P. A., Levidou, G., Trigka, E., Prekete, N., Κάρλου, Μ., Thymara, I., Sakellariou, S., Fragkou, P. C., Isaiadis, D., Pavlopoulos, P. M., et al. (2012) · British Journal of Urology · doi:10.1111/j.1464-410x.2012.11569.x · Cited by 61
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“This antagonism may explain the modest apoptotic and largely cytostatic effect of MEK/ERK inhibitors in KRAS mutant tumor xenografts (18) as well as predominantly stable disease in patient studies (6, 7).”
BackgroundRAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas
Serrano, C., Romagosa, C., Hernández‐Losa, J., Simonetti, S., Valverde, C., Moliné, T., Somoza, R., Pérez, M., Vélez, R., Vergés, R., et al. (2016) · Cancer · doi:10.1002/cncr.29733 · Cited by 59
Nayak, B. K., Féliers, D., Sudarshan, S., Friedrichs, W. E., Day, R. T., New, D. D., Fitzgerald, J. P., Eid, A. A., DeNapoli, T. S., Parekh, D. J., et al. (2012) · Oncogene · doi:10.1038/onc.2012.333 · Cited by 60
“In cells with high ERK activity, phosphorylation of 4E-BP1 may be unaffected by mTORC2 inhibition (24).”
Cai, W., Ye, Q., & She, Q. (2014) · Oncotarget · doi:10.18632/oncotarget.2109 · Cited by 59
“com/oncotarget cancer cell motility and metastasis[19] [11, 39].”
InfluentialSelf-citationTargeting Translation Dependence in Cancer
Malina, A., Cencic, R., & Pelletier, J. (2011) · Oncotarget · doi:10.18632/oncotarget.218 · Cited by 58
“Moreover, the expression of a nonphosphorylatable, constitutively active 4E-BP1 suppressed growth of tumors driven by PI3K and K-Ras mutations [111].”
BackgroundCotargeting the PI3K and RAS Pathways for the Treatment of Neuroendocrine Tumors
Valentino, J. D., Li, J., Zaytseva, Y. Y., Mustain, W. C., Elliott, V. A., Kim, J. T., Harris, J. W., Campbell, K., Weiss, H. L., Wang, C., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1897 · Cited by 60
“Furthermore, cotargeting of these pathways can enhance the therapeutic response (15-17).”
Translational Regulation in Nutrigenomics
Liu, B., & Qian, S. (2011) · Advances in Nutrition · doi:10.3945/an.111.001057 · Cited by 55
“In contrast, inhibition of eIF4E by either constitutively active 4E-BP1 or small interfering RNA led to the repression of tumor growth derived from PI3K signaling mutations (89,90).”
BackgroundHaarberg, H. E., Paraiso, K. H. T., Wood, E. R., Rebecca, V. W., Sondak, V. K., Koomen, J. M., & Smalley, K. S. M. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-1003 · Cited by 58
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Self-citationAdvances in targeted and immunobased therapies for colorectal cancer in the genomic era
Seow, H. F., Yip, W. K., & Fifis, T. (2016) · OncoTargets and Therapy · doi:10.2147/ott.s95101 · Cited by 54
Caumanns, J. J., van Wijngaarden, A. P., Kol, A., Meersma, G. J., Jalving, M., Bernards, R., van der Zee, A. G. J., Wisman, G. B. A., & de Jong, S. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.07.004 · Cited by 51
Venkannagari, S., Fiskus, W. C., Peth, K., Atadja, P. W., Hidalgo, M. M., Maitra, A., & Bhalla, K. N. (2012) · Oncotarget · doi:10.18632/oncotarget.724 · Cited by 50
“Loss of 4EBP1 was shown to increase tumorigenesis due to p53 inactivation, whereas an increase in 4EBP1 activity inhibited tumors driven by co-expression of mutant KRAS and PI3K [16, 17].”
Liu, J., Stevens, P. D., Eshleman, N. E., & Gao, T. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.492371 · Cited by 52
“Furthermore, the phosphorylation status of 4E-BP1 has been identified as a biomarker to indicate the efficacyof anticancer treatmentsbecauseacompletedephosphorylation of 4E-BP1 is required to effectively inhibit cancer cell growth in vitro and in vivo (11).”
BackgroundPhosphorylated 4E‐binding protein 1 (p‐4E‐BP1): a novel prognostic marker in human astrocytomas
Korkolopoulou, P. A., Levidou, G., El-Habr, E. A., Piperi, C., Adamopoulos, C., Samaras, V. D., Boviatsis, E. I., Thymara, I., Trigka, E., Sakellariou, S., et al. (2012) · Histopathology · doi:10.1111/j.1365-2559.2012.04236.x · Cited by 49
“This is consistent with in-vitro data, substantiating the emerging role of ERK signalling in regulating 4E-BP1.(33) Despite the coexpression of p-mTOR, p-p70S6K, and p-4E-BP1, the three proteins were topographically distinct.”
ResultBcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer
Wu, D., Huang, C.-C., Chang, S.-W., Chen, T. H., & Lee, H. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.170 · Cited by 48
Silva, J. M., Bulman, C. A., & McMahon, M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0224-t · Cited by 48
Translation Initiation Factor eIF4E Is a Target for Tumor Cell Radiosensitization
Hayman, T. J., Williams, E. S., Jamal, M., Shankavaram, U. T., Camphausen, K. A., & Tofilon, P. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0329 · Cited by 49
“eIF4E serves as a funnel point (31) for a number of oncogenic pathways reflecting the consequences of activation of RTKs along with Ras and PI3K pathways (5, 32, 33).”
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“, 2010) were screened using a cap-dependent translation-based luciferase reporter assay (She et al., 2010; Wang et al., 2017).”
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“We took advantage of a doxycycline (dox)-inducible mutant 4E-BP1 4Ala (4E-BP1 4A) that constitutively binds eIF4E to inhibit cap-dependent translation (22, 23).”
Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models
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Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition
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“Although mTORC1 seems to be the chief phosphorylation pathway of 4EBP1, other unidentified kinases and biochemical mechanisms are also involved such as cyclin-dependent kinase 1, ataxia-telangiectasia mutated/p53, RAS/extracellular signal-regulated kinase1/2 and other collateral signaling pathways [10, 12].”
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“Some of the explanations that were found underlie this synergy and include downstream convergence of translational control of survival signaling [96] and regulation of the balance of pro-apoptotic and anti-apoptotic members of the Bcl-2 family (e.”
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“Growth factor signaling cascades modulate the activity of translation initiation factors by controlling their phosphorylation (Raught et al., 2004; Svitkin et al., 2005; Mamane et al., 2006; She et al., 2010).”
BackgroundAlternative dosing of dual PI3K and MEK inhibition in cancer therapy
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“and α isoform selective PI3K inhibitors, whereas cell lines with concurrent KRASmutations aremore resistant to these inhibitors.(8,9) Several nonclinical studies have shown that PTEN-deficient tumors preferentially depend on the β isoform of PI3K for survival and respond to β-specific, but not α-specific, inhibitors.”
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Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer
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Histone Deacetylase Inhibitors in Tumor Immunotherapy
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“Deregulation of cap-dependent translation by mTOR-mediated phosphorylation of 4E-BP1 plays an important role in cancer progression 17,29,30,45 .”
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Renal cancer-selective Englerin A induces multiple mechanisms of cell death and autophagy
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“…mRNA translation through activation of ribosomal protein S6 (RPS6) and elongation initiation factor 4e (eIF4e), as well as inactivation of translational repressor 4E-binding protein 1, allowing for cap-dependent translation initiation (Gwin et al., 2011; Romeo et al., 2013; She et al., 2010).”
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Rapamycin Resistance: mTORC1 Substrates Hold Some of the Answers
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“com/oncotarget in HCT116 cells, as the inhibition of both pathways efficiently downregulates phospho-4E-BP1 [43, 44].”
InfluentialThe Identification of Perillyl Alcohol Glycosides with Improved Antiproliferative Activity
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Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS -Wild-Type Melanoma Cell Lines
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“Mechanistically, it appears that MAPK and PI3K/AKT/mTOR converge on key cell survival hubs, with their combined inhibition leading to increased apoptosis (43).”
BackgroundThe “SWOT” of BRAF Inhibition in Melanoma: RAF Inhibitors, MEK Inhibitors or Both?
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“This might suggest the activation of 4E-BP1 via MEK or AKT signalling without the need of mTOR integration [38] (Fig.”
Background
Metadata
- 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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