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Cited by 96PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingColorectal Cancer Treatments and Studies

MNK Inhibition Sensitizes KRAS -Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression

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Knight, John R.P., Alexandrou, Constantinos, Skalka, George L., Vlahov, Nikola, Pennel, Kathryn, Officer, Leah, Teodosio, Ana, Kanellos, Georgios +31 more·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-0652PMC PMC7611341

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Abstract

Abstract KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC–dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. Significance: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer. This article is highlighted in the In This Issue feature, p. 995

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  • Translational control plays a critical role in all steps of cancer progression.

    “Translational control plays a critical role in all steps of cancer progression, and most oncogenic signaling pathways converge to enhance the translational capacity of tumor cells (30–32).”

    From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [31]

    The Introduction says that deregulated mRNA translation sustains cancer-cell proliferation and oncogene expression, and that eIF4E phosphorylation is downstream of many oncogenic pathways. It does not establish a critical role for translational control in all steps of cancer progression, or that most oncogenic pathways converge to enhance tumor cells’ translational capacity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Most oncogenic signaling pathways converge to enhance the translational capacity of tumor cells.

    “Translational control plays a critical role in all steps of cancer progression, and most oncogenic signaling pathways converge to enhance the translational capacity of tumor cells (30–32).”

    From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [31]

    The Introduction says that many oncogenic pathways signal to eIF4E phosphorylation and that KRAS activation enhances protein synthesis. It supports a link between oncogenic signaling and translation, but does not establish that most oncogenic pathways converge to enhance tumor cells’ translational capacity. (LLM, conf=0.85)

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  1. [1]Guinney J Dienstmann R Wang X de Reynies A Schlicker A Soneson C The consensus molecular subtypes of colorectal cancer Nat Med United States 2015 21 1350 6 26457759 PMC4636487
  2. [2]Yaeger R Chatila WK Lipsyc MD Hechtman JF Cercek A Sanchez-Vega F Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer Cancer Cell Elsevier 2018 33 125 136 e3 10.1016/j.ccell.2017.12.004 Available from [Internet] 29316426 PMC5765991 · DOI · Paper page
  3. [3]DeStefanis RA Kratz JD Emmerich PB Deming DA Targeted Therapy in Metastatic Colorectal Cancer: Current Standards and Novel Agents in Review Curr Colorectal Cancer Rep 2019 15 61 9 10.1007/s11888-019-00430-6 Available from [Internet] 31130830 PMC6528813 · DOI
  4. [4]Hong DS Fakih MG Strickler JH Desai J Durm GA Shapiro GI KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors N Engl J Med Massachusetts Medical Society 2020 383 1207 17 10.1056/NEJMoa1917239 Available from [Internet] 32955176 PMC7571518 · DOI · Paper page
  5. [5]Faller WJ Jackson TJ Knight JRP Ridgway RA Jamieson T Karim SA MTORC1-mediated translational elongation limits intestinal tumour initiation and growth Nature 2015 517 PMC4304784 25383520
  6. [6]Yuksekkaya H Yucel A Gumus M Esen H Toy H Familial Adenomatous Polyposis; Succesful Use of Sirolimus Am J Gastroenterol United States 2016 1040 1 27356835
  7. [7]Ng K Tabernero J Hwang J Bajetta E Sharma S Del Prete SA Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens Clin Cancer Res 2013 19 3987 95 23743569 PMC3725595
  8. [8]Spindler K-LG Sorensen MM Pallisgaard N Andersen RF Havelund BM Ploen J Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer: outcome and results of KRAS mutational analysis in plasma Acta Oncol 2013 52 963 70 Available from: [Internet] 23514584
  9. [9]Di Nicolantonio F Arena S Tabernero J Grosso S Molinari F Macarulla T Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus J Clin Invest American Society for Clinical Investigation 2010 120 2858 66 Available from: [Internet] 20664172 PMC2912177
  10. [10]Hung KE Maricevich MA Richard LG Chen WY Richardson MP Kunin A Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment Proc Natl Acad Sci 2010 107 1565 1570 Available from: [Internet] http://www.pnas.org/content/107/4/1565.abstract 20080688 PMC2824379
  11. [11]Park JH McMillan DC Powell AG Richards CH Horgan PG Edwards J Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer Clin Cancer Res United States 2015 21 882 8 25473000
  12. [13]Katsumura KR Yang C Boyer ME Li L Bresnick EH Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA‐2 EMBO Rep 2014 15 938 947 [Internet] Available from: http://embor.embopress.org/content/15/9/938.abstract 25056917 PMC4198037
  13. [14]Park M-T Kim M-J Suh Y Kim R-K Kim H Lim E-J Novel signaling axis for ROS generation during K-Ras-induced cellular transformation Cell Death Differ 2014 21 1185 97 [Internet], Available from: 24632950 PMC4085525
  14. [15]Morley SJ McKendrick L Involvement of Stress-activated Protein Kinase and p38/RK Mitogen-activated Protein Kinase Signaling Pathways in the Enhanced Phosphorylation of Initiation Factor 4E in NIH 3T3 Cells J Biol Chem 1997 272 17887 93 [Internet] Available from: http://www.jbc.org/content/272/28/17887.abstract 9211946
  15. [16]Proud CG Mnks, eIF4E phosphorylation and cancer Biochim Biophys Acta - Gene Regul Mech 2015 1849 766 73 [Internet] Available from: http://www.sciencedirect.com/science/article/pii/S1874939914002612 25450520
  16. [17]Ueda T Watanabe-Fukunaga R Fukuyama H Nagata S Fukunaga R Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development Mol Cell Biol 2004 24 6539 49 10.1128/MCB.24.15.6539-6549.2004 [Internet], Available from: 15254222 PMC444855 · DOI · Paper page
  17. [18]Waskiewicz AJ Flynn A Proud CG Cooper JA Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 EMBO J England 1997 16 1909 20 9155017 PMC1169794
  18. [19]Furic L Rong L Larsson O Koumakpayi IH Yoshida K Brueschke A eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression Proc Natl Acad Sci U S A 2010 107 14134 9 [Internet], Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2922605&tool=pmcentrez&rendertype=abstract 20679199 PMC2922605
  19. [20]Geter PA Ernlund AW Bakogianni S Alard A Arju R Giashuddin S Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming Genes Dev 2017 31 2235 49 29269484 PMC5769768
  20. [21]Bell JB Eckerdt FD Alley K Magnusson LP Hussain H Bi Y MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma Mol Cancer Res 2016 14 984 93 10.1158/1541-7786.MCR-16-0172 [Internet], Available from: 27364770 PMC5082426 · DOI
  21. [22]Zhan Y Guo J Yang W Goncalves C Rzymski T Dreas A MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma J Clin Invest 2017 127 4179 92 29035277 PMC5663367
  22. [23]Kosciuczuk EM Saleiro D Kroczynska B Beauchamp EM Eckerdt F Blyth GT Merestinib blocks Mnk kinase activity in acute myeloid leukemia progenitors and exhibits antileukemic effects in vitro and in vivo Blood 2016 128 410 4 27307295 PMC4957163
  23. [24]Xu Y Poggio M Jin HY Shi Z Forester CM Wang Y Translation control of the immune checkpoint in cancer and its therapeutic targeting Nat Med 2019 25 301 11 10.1038/s41591-018-0321-2 Available from, [Internet] 30643286 PMC6613562 · DOI · Paper page
  24. [25]Ueda T Sasaki M Elia AJ Chio IIC Hamada K Fukunaga R Combined deficiency for MAP kinase-interacting kinase 1 and 2 (Mnk1 and Mnk2) delays tumor development Proc Natl Acad Sci 2010 107 13984 13990 [Internet], Available from: http://www.pnas.org/content/107/32/13984.abstract 20679220 PMC2922567
  25. [26]Reich SH Sprengeler PA Chiang GG Appleman JR Chen J Clarine J Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition J Med Chem American Chemical Society 2018 61 3516 40 10.1021/acs.jmedchem.7b01795 Available from, [Internet] 29526098 · DOI
  26. [27]Scheper GC van Kollenburg B Hu J Luo Y Goss DJ Proud CG Phosphorylation of Eukaryotic Initiation Factor 4E Markedly Reduces Its Affinity for Capped mRNA J Biol Chem 2002 277 3303 9 [Internet], Available from: http://www.jbc.org/content/277/5/3303.abstract 11723111
  27. [28]McKendrick L Morley SJ Pain VM Jagus R Joshi B Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at Ser209 is not required for protein synthesis in vitro and in vivo Eur J Biochem John Wiley & Sons, Ltd 2001 268 5375 85 10.1046/j.0014-2956.2001.02478.x Available from, [Internet], (10.1111) 11606200 · DOI
  28. [29]Sansom OJ Meniel V Wilkins JA Cole AM Oien KA Marsh V Loss of Apc allows phenotypic manifestation of the transforming properties of an endogenous K-ras oncogene in vivo Proc Natl Acad Sci U S A National Academy of Sciences 2006 9 07 103 14122 7 2006, [Internet], Available from: 16959882 PMC1599922
  29. [30]Haigis KM Kendall KR Wang Y Cheung A Haigis MC Glickman JN Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon Nat Genet 2008 3 30 40 600 8 2008, [Internet], Available from 18372904 PMC2410301
  30. [31]Poulin EJ Bera AK Lu J Lin Y-J Strasser SD Paulo JA Tissue-Specific Oncogenic Activity of KRAS<sup>A146T</sup> Cancer Discov 2019 9 738 755 [Internet], Available from: http://cancerdiscovery.aacrjournals.org/content/9/6/738.abstract 30952657 PMC6548671
  31. [32]Raught B Peiretti F Gingras AC Livingstone M Shahbazian D Mayeur GL Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases EMBO J 2004 23 1761 9 15071500 PMC394247
  32. [33]Raught B Gingras AC Gygi SP Imataka H Morino S Gradi A Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI EMBO J 2000 19 434 44 [Internet], Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=305580&tool=pmcentrez&rendertype=abstract 10654941 PMC305580
  33. [34]Shahbazian D Roux PP Mieulet V Cohen MS Raught B Taunton J The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity EMBO J European Molecular Biology Organization 2006 25 2781 91 10.1038/sj.emboj.7601166 Available from, [Internet] 16763566 PMC1500846 · DOI
  34. [35]Proud CG Phosphorylation and Signal Transduction Pathways in Translational Control Cold Spring Harb Perspect Biol United States 2019 11 PMC6601458 29959191
  35. [36]Roper J Tammela T Cetinbas NM Akkad A Roghanian A Rickelt S In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis Nat Biotechnol Nature Publishing Group, a division of Macmillan Publishers Limited 2017 35 569 10.1038/nbt.3836 Available from, All Rights Reserved [Internet] 28459449 PMC5462879 · DOI
  36. [37]Gay DM Ridgway RA Müller M Hodder MC Hedley A Clark W Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer Nat Commun 2019 10 723 10.1038/s41467-019-08586-3 Available from, [Internet] 30760720 PMC6374445 · DOI
  37. [38]Bianchini A Loiarro M Bielli P Busà R Paronetto MP Loreni F Phosphorylation of eIF4E by MNKs supports protein synthesis, cell cycle progression and proliferation in prostate cancer cells Carcinogenesis 2008 29 2279 88 10.1093/carcin/bgn221 Available from, [Internet] 18809972 · DOI
  38. [39]ur Rasool R Rah B Amin H Nayak D Chakraborty S Rawoof A Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E Sci Rep 2016 6 18800 10.1038/srep18800 [Internet], The Author(s), Available from 26728896 PMC4700468 · DOI
  39. [40]Sansom OJ Meniel VS Muncan V Phesse TJ Wilkins JA Reed KR Myc deletion rescues Apc deficiency in the small intestine Nature Nature Publishing Group 2007 446 676 10.1038/nature05674 Available from, [Internet] 17377531 · DOI
  40. [41]Gildish I Manor D David O Sharma V Williams D Agarwala U Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice Learn Mem Cold Spring Harbor Laboratory Press 2012 19 116 25 [Internet], Available from 22366775 PMC3293518
  41. [42]Zuberek J Wyslouch-Ciesyzynska A Niedzwiecka A Dadlez M Stepinski J Augustyniak W Phosphorylation of eIF4E attenuates its interaction with mRNA 5′ cap analogs by electrostatic repulsion: Intein-mediated protein ligation strategy to obtain phosphorylated protein RNA 2003 9 52 61 [Internet], Available from: http://rnajournal.cshlp.org/content/9/1/52.abstract 12554876 PMC1370370
  42. [44]Bruno PM Liu Y Park GY Murai J Koch CE Eisen TJ A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress Nat Med 2017 2 27 23 461 71 [Internet], 2017 28263311 PMC5520548
  43. [45]Bash-Imam Z Thérizols G Vincent A Lafôrets F Polay Espinoza M Pion N Translational reprogramming of colorectal cancer cells induced by 5-fluorouracil through a miRNA-dependent mechanism Oncotarget Impact Journals LLC 2017 8 46219 33 [Internet], Available from: 28515355 PMC5542262
  44. [46]Wiegering A Uthe FW Jamieson T Ruoss Y Huttenrauch M Kuspert M Targeting Translation Initiation Bypasses Signaling Crosstalk Mechanisms That Maintain High MYC Levels in Colorectal Cancer Cancer Discov United States 2015 5 768 81 25934076 PMC5166973
  45. [47]Fabregat A Sidiropoulos K Viteri G Forner O Marin-Garcia P Arnau V Reactome pathway analysis: a high-performance in-memory approach BMC Bioinformatics 2017 18 142 10.1186/s12859-017-1559-2 Available from, [Internet] 28249561 PMC5333408 · DOI
  46. [49]Hall Z Ament Z Wilson CH Burkhart DL Ashmore T Koulman A Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer Cancer Res 2016 76 4608 4618 [Internet], Available from: http://cancerres.aacrjournals.org/content/76/16/4608.abstract 27335109
  47. [50]Mohammed A Yarla NS Madka V Rao CV Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives Int J Mol Sci MDPI 2018 19 2332 [Internet], Available from: 30096840 PMC6121559
  48. [51]Jackstadt R van Hooff SR Leach JD Cortes-Lavaud X Lohuis JO Ridgway RA Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis Cancer Cell 2019 36 319 336 e7 [Internet], Available from: http://www.sciencedirect.com/science/article/pii/S153561081930371X 31526760 PMC6853173
  49. [53]Murphy DJ Junttila MR Pouyet L Karnezis A Shchors K Bui DA Distinct Thresholds Govern Myc’s Biological Output In Vivo Cancer Cell 2008 14 447 57 [Internet], Available from: http://www.sciencedirect.com/science/article/pii/S153561080800367X 19061836 PMC2723751
  50. [54]West MJ Stoneley M Willis AE Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway Oncogene England 1998 17 769 80 9715279
  51. [55]Wall M Poortinga G Hannan KM Pearson RB Hannan RD McArthur GA Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation Blood 2008 112 2305 17 10.1182/blood-2007-09-111856 [Internet], Available from 18621930 · DOI
  52. [56]Csibi A Lee G Yoon S-O Tong H Ilter D Elia I The mTORC1/S6K1 Pathway Regulates Glutamine Metabolism through the eIF4B-Dependent Control of c-Myc Translation Curr Biol 2014 24 2274 80 [Internet], Available from: http://www.sciencedirect.com/science/article/pii/S0960982214009853 25220053 PMC4190129
  53. [57]Shi Y Frost P Hoang B Yang Y Fukunaga R Gera J MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells Oncogene England 2013 32 190 7 22370634 PMC3401333
  54. [58]Schmidt S Gay D Uthe FW Denk S Paauwe M Matthes N A MYC–GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer Nat Cell Biol 2019 21 1413 24 10.1038/s41556-019-0408-0 Available from, [Internet] 31685988 PMC6927814 · DOI
  55. [59]Lineham E Tizzard GJ Coles SJ Spencer J Morley SJ Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells Oncotarget United States 2018 9 14148 59 29581834 PMC5865660
  56. [60]Marzec M Liu X Wysocka M Rook AH Odum N Wasik MA Simultaneous Inhibition of mTOR-Containing Complex 1 (mTORC1) and MNK Induces Apoptosis of Cutaneous T-Cell Lymphoma (CTCL) Cells PLoS One Public Library of Science 2011 6 e24849 10.1371/journal.pone.0024849 Available from, [Internet] 21949767 PMC3174990 · DOI
  57. [61]Altman JK Szilard A Konicek BW Iversen PW Kroczynska B Glaser H Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors Blood 2013 121 3685 3681 [Internet], Available from: http://www.bloodjournal.org/content/early/2013/03/18/blood-2013-01-477216.abstract PMC3643766 23509154
  58. [62]Wen Q Wang W Luo J Chu S Chen L Xu L CGP57380 enhances efficacy of RAD001 in non-small cell lung cancer through abrogating mTOR inhibition-induced phosphorylation of eIF4E and activating mitochondrial apoptotic pathway Oncotarget United States 2016 7 27787 801 27050281 PMC5053688
  59. [63]Lock R Ingraham R Maertens O Miller AL Weledji N Legius E Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers J Clin Invest United States 2016 126 2181 90 27159396 PMC4887164
  60. [64]Fortin CF Mayer TZ Cloutier A McDonald PP Translational control of human neutrophil responses by MNK1 J Leukoc Biol United States 2013 94 693 703 23401599
  61. [65]Buxade M Parra JL Rousseau S Shpiro N Marquez R Morrice N The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1 Immunity United States 2005 23 177 89 16111636
  62. [66]Robichaud N Hsu BE Istomine R Alvarez F Blagih J Ma EH Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils Proc Natl Acad Sci 2018 115 E2202 9 10.1073/pnas.1717439115 [Internet], Available from: 29463754 PMC5877985 · DOI
  63. [67]Fan S Ramalingam SS Kauh J Xu Z Khuri FR Sun S-Y Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues Cancer Biol Ther Taylor & Francis 2009 8 1463 9 10.4161/cbt.8.15.8960 Available from, [Internet] 19483468 PMC2804981 · DOI
  64. [68]Network TCGA Comprehensive genomic characterization of head and neck squamous cell carcinomas Nature 2015 517 576 10.1038/nature14129 [Internet], The Author(s), Available from 25631445 PMC4311405 · DOI
  65. [70]El Marjou F Janssen KP Chang BHJ Li M Hindie V Chan L Tissue-specific and inducible Cre-mediated recombination in the gut epithelium Genesis 2004 39 186 93 15282745
  66. [71]Fisher S Barry A Abreu J Minie B Nolan J Delorey TM A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries Genome Biol 2011 12 R1 10.1186/gb-2011-12-1-r1 Available from, [Internet] 21205303 PMC3091298 · DOI

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Authors
Knight, J. R. P., Alexandrou, C., Skalka, G. L., Vlahov, N., Pennel, K., Officer, L., Teodosio, A., Kanellos, G., Gay, D. M., May-Wilson, S., Smith, E. M., Najumudeen, A. K., Gilroy, K., Ridgway, R. A., Flanagan, D. J., Smith, R. C. L., McDonald, L., MacKay, C., Cheasty, A., McArthur, K., Stanway, E., Leach, J. D., Jackstadt, R., Waldron, J. A., Campbell, A. D., Vlachogiannis, G., Valeri, N., Haigis, K. M., Sonenberg, N., Proud, C. G., Jones, N. P., Swarbrick, M. E., McKinnon, H. J., Faller, W. J., Le Quesne, J., Edwards, J., Willis, A. E., Bushell, M., & Sansom, O. J.
Affiliations
  • Cancer Research UK Scotland Institute (GB)
  • University of Cambridge (GB)
  • University of Glasgow (GB)
  • 2MRC Toxicology Unit, University of Cambridge, Cambridge, United Kingdom.
  • Cancer Research UK (GB)
  • 1CRUK Beatson Institute, Glasgow, United Kingdom.
  • Institute of Cancer Research (GB)
  • Royal Marsden NHS Foundation Trust (GB)
  • Brigham and Women's Hospital (US)
  • McGill University (CA)
  • South Australian Health and Medical Research Institute (AU)
Corresponding author
Sansom, Owen J.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2020-12-16
Volume
11
Issue
5
Pages
1228-1247
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-0652
PMC
PMC7611341
OpenAlex
W3111047021
Cited by
96
References
5
Citations by year
2026: 12 · 2025: 21 · 2024: 19 · 2023: 22 · 2022: 17 · 2021: 4 · 2020: 1
FWCI
3.57
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • eScholarship@McGill (McGill) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
Funders
  • CRUK (A17196, A24388, A21139, A25045, A29055, C596/A17196)
  • European Research Council ColonCan (311301)
  • Wellcome Trust (201487)
  • MRC Clinical Research Predoctoral Training Fellowship (MR/N021800/1)
  • MRC Fellowship (MR/R502327/1)
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 › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
KRAS G12D mutation, colorectal cancer, mTORC1 inhibition, rapamycin, eIF4E phosphorylation, c-Myc, translation initiation, drug resistance, patient-derived organoids, combination therapy, cancer-specific survival
MeSH terms
MTOR Inhibitors, Animals, Disease Models, Animal, Humans, Mice, Inbred C57BL, Phosphorylation, Colorectal Neoplasms, Protein Serine-Threonine Kinases, Eukaryotic Initiation Factor-4E, Intracellular Signaling Peptides and Proteins, Mice

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