Skip to main content

Targeting Translation of mRNA as a Therapeutic Strategy in Cancer

Abstract

Purpose of Review

To highlight recent results in targeting mRNA translation and discuss the results and prospects of translation inhibitors in cancer therapy.

Recent Findings

Until recently, inhibitors of mRNA translation have been thought to likely lack a therapeutic window. In 2012, the Food and Drug Administration (FDA) approved omacetaxine mepesuccinate (homoharringtonine) for the treatment of adults with chronic myelogenous leukemia (CML) who are resistant to at least two tyrosine kinase inhibitors. Since then, a few drugs, notably tomivosertib (eFT-508), selinexor (KPT-330), and ribavirin, have entered clinical trials. These drugs are known to inhibit mRNA translation. More recently, a number of interesting studies report that discrete subsets of proteins in cancer cells may be selectively targeted at the translation step, through inhibiting signals such as phospho-4E-BP1, eIF4A, and eIF4E. Promising therapies using these strategies have demonstrated potent anti-tumor activity in preclinical cancer models.

Summary

The growing number of translation inhibitors with diverse mechanisms, coupled with emerging insights into translational regulation of different cancer-promoting genes, suggests a bright new horizon for the field of therapeutic targeting of mRNA translation in cancer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.

    Haghighat A, Mader S, Pause A, Sonenberg N. Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. EMBO J. 1995;14:5701–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. 2.

    Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 1999;13:1422–37.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. 3.

    Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem. 1997;272:26457–63.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002;16:1472–87.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. 5.

    Shin S, Wolgamott L, Roux PP, Yoon SO. Casein kinase 1epsilon promotes cell proliferation by regulating mRNA translation. Cancer Res. 2014;74:201–11.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    •• Deng C, Lipstein MR, Scotto L, Jirau Serrano XO, Mangone MA, Li S, et al. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kdelta and CK1epsilon in hematological malignancies. Blood. 2017;129:88–99 The results demonstrate that clinically available drugs, for example, umbralisib and carfilzomib, can be combined in rational combinations to synergistically inhibit translation. Potentially many other combinations can be identified to silence translation, thus avoiding the delays in developing brand new translation inhibitors of uncertain clinical value.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. 7.

    Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med. 2013;3.

  8. 8.

    Andresen C, Helander S, Lemak A, Farès C, Csizmok V, Carlsson J, et al. Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding. Nucleic Acids Res. 2012;40:6353–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. 9.

    Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533–7.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28:3360–5.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Johnson NA, Slack GW, Savage KJ, Connors JM, Ben-Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3452–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. 12.

    Hu S, Xu-Monette ZY, Tzankov A, Green T, Wu L, Balasubramanyam A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121:4021–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. 13.

    Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Lin P, Medeiros LJ. High-grade B-cell lymphoma/leukemia associated with t(14;18) and 8q24/MYC rearrangement: a neoplasm of germinal center immunophenotype with poor prognosis. Haematologica. 2007;92:1297–301.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Copie-Bergman C, Cuilliere-Dartigues P, Baia M, Briere J, Delarue R, Canioni D, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood. 2015;126:2466–74.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Carrasco DR, Tonon G, Huang Y, Zhang Y, Sinha R, Feng B, et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell. 2006;9:313–25.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014;28:1725–35.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. 18.

    Walker BA, Wardell CP, Murison A, Boyle EM, Begum DB, Dahir NM, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015;6:6997.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. 19.

    Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T, et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 2011;25:1026–35.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. 20.

    Schleger, C., Verbeke, C., Hildenbrand, R., Zentgraf, H. & Bleyl, U. c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: incidence, mechanisms, and clinical significance. Mod Pathol 15, 462–469 (2002).

  21. 21.

    Hessmann E, Schneider G, Ellenrieder V, Siveke JT. MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. Oncogene. 2016;35:1609–18.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Chen R, Dawson DW, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, et al. Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma. Lab Investig. 2015;95:43–55.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Zhang M, et al. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget. 2016.

  24. 24.

    Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature. 2014;513:65–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. 25.

    Iwasaki S, Floor SN, Ingolia NT. Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor. Nature. 2016;534:558–61.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. 26.

    Low WK, Dang Y, Schneider-Poetsch T, Shi Z, Choi NS, Merrick WC, et al. Inhibition of eukaryotic translation initiation by the marine natural product pateamine a. Mol Cell. 2005;20:709–22.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Manier S, et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci Transl Med. 2017;9.

  28. 28.

    Kim YR, et al. Silencing oncogene translation using pateamine a analogues as a novel therapeutic strategy for c-Myc driven lymphoma. Blood. 2017;130:–4111.

  29. 29.

    •• Xu Y, Poggio M, Jin HY, Shi Z, Forester CM, Wang Y, et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat Med. 2019;25:301–11 This paper demonstrates that eFT508, which is now in early phase clinical trials, can preferentially inhibit translation of PD-L1 and induce tumor regression in animal models. This is a significant step forward in establishing that targeting translation can invoke two mechanisms to control tumor, by directly inducing apoptosis and indirectly stimulating the anti-tumor immune response.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. 30.

    •• Cerezo M, Guemiri R, Druillennec S, Girault I, Malka-Mahieu H, Shen S, et al. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat Med. 2018;24:1877–86 This paper is the first to convincingly demonstrate that targeting eIF4F can preferentially inhibit translation of STAT1, leading to reduced transcription of PD-L1 and stimulation of anti-tumor immune response.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Ingolia NT. Ribosome footprint profiling of translation throughout the genome. Cell. 2016;165:22–33.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. 32.

    Gonzalez C, Sims JS, Hornstein N, Mela A, Garcia F, Lei L, et al. Ribosome profiling reveals a cell-type-specific translational landscape in brain tumors. J Neurosci. 2014;34:10924–36.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. 33.

    Simsek D, et al. The mammalian ribo-interactome reveals ribosome functional diversity and heterogeneity. Cell. 2017;169:1051–1065 e18.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. 34.

    Leppek K, Das R, Barna M. Functional 5' UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol. 2018;19:158–74.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Truitt ML, Conn CS, Shi Z, Pang X, Tokuyasu T, Coady AM, et al. Differential requirements for eIF4E dose in normal development and cancer. Cell. 2015;162:59–71.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. 36.

    Yun S, Vincelette ND, Knorr KLB, Almada LL, Schneider PA, Peterson KL, et al. 4EBP1/c-MYC/PUMA and NFkappaB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells. Blood. 2016;127:2711–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. 37.

    Zhang C, et al. Icariside II, a natural mTOR inhibitor, disrupts aberrant energy homeostasis via suppressing mTORC1-4E-BP1 axis in sarcoma cells. Oncotarget. 2016.

  38. 38.

    Demosthenous C, Han JJ, Stenson MJ, Maurer MJ, Wellik LE, Link B, et al. Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma. Oncotarget. 2015;6:9488–501.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, et al. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia. Am J Hematol. 2016;91:400–5.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Kuo SH, Hsu CH, Chen LT, Lu YS, Lin CH, Yeh PY, et al. Lack of compensatory pAKT activation and eIF4E phosphorylation of lymphoma cells towards mTOR inhibitor, RAD001. Eur J Cancer. 2011;47:1244–57.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. 42.

    Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485:55–61.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. 43.

    Hwang BY, Su BN, Chai H, Mi Q, Kardono LB, Afriastini JJ, et al. Silvestrol and episilvestrol, potential anticancer rocaglate derivatives from Aglaia silvestris. J Org Chem. 2004;69:3350–8.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Bordeleau ME, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118.

  45. 45.

    Cencic R, et al. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLoS One. 2009;4.

  46. 46.

    Lucas DM, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009;113.

  47. 47.

    Babendure JR, Babendure JL, Ding JH, Tsien RY. Control of mammalian translation by mRNA structure near caps. RNA. 2006;12.

  48. 48.

    Chen W-L, Pan L, Kinghorn AD, Swanson SM, Burdette JE. Silvestrol induces early autophagy and apoptosis in human melanoma cells. BMC Cancer. 2016;16:17.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. 49.

    Kogure T, Kinghorn AD, Yan I, Bolon B, Lucas DM, Grever MR, et al. Therapeutic potential of the translation inhibitor silvestrol in hepatocellular cancer. PLoS One. 2013;8:e76136.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. 50.

    Oblinger JL, Burns SS, Huang J, Pan L, Ren Y, Shen R, et al. Overexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation. Exp Neurol. 2018;299:299–307.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Kim S, et al. Silvestrol, a potential anticancer rocaglate derivative from Aglaia foveolata, induces apoptosis in LNCaP cells through the mitochondrial/apoptosome pathway without activation of executioner caspase-3 or -7. Anticancer Res. 2007;27:2175–83.

    PubMed  CAS  PubMed Central  Google Scholar 

  52. 52.

    Cencic R, Carrier M, Trnkus A, Porco JA Jr, Minden M, Pelletier J. Synergistic effect of inhibiting translation initiation in combination with cytotoxic agents in acute myelogenous leukemia cells. Leuk Res. 2010;34:535–41.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Daker M, et al. Inhibition of nasopharyngeal carcinoma cell proliferation and synergism of cisplatin with silvestrol and episilvestrol isolated from Aglaia stellatopilosa. Exp Ther Med. 2016;11:2117–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. 54.

    Gupta SV, Sass EJ, Davis ME, Edwards RB, Lozanski G, Heerema NA, et al. Resistance to the translation initiation inhibitor silvestrol is mediated by ABCB1/P-glycoprotein overexpression in acute lymphoblastic leukemia cells. AAPS J. 2011;13:357–64.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. 55.

    Northcote PT, Blunt JW, Munro MHG. Pateamine: a potent cytotoxin from the New Zealand marine sponge, Mycale sp. Tetrahedron Lett. 1991;32:6411–4.

    Article  CAS  Google Scholar 

  56. 56.

    Low WK, et al. Isolation and identification of eukaryotic initiation factor 4A as a molecular target for the marine natural product pateamine A. Methods Enzymol. 2007;431:303–24 (Academic Press.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Romo D, Rzasa RM, Shea HA, Park K, Langenhan JM, Sun L, et al. Total synthesis and immunosuppressive activity of (−)-pateamine A and related compounds: implementation of a β-lactam-based macrocyclization. J Am Chem Soc. 1998;120:12237–54.

    Article  CAS  Google Scholar 

  58. 58.

    Romo D, Choi NS, Li S, Buchler I, Shi Z, Liu JO. Evidence for separate binding and scaffolding domains in the immunosuppressive and antitumor marine natural product, pateamine a: design, synthesis, and activity studies leading to a potent simplified derivative. J Am Chem Soc. 2004;126:10582–8.

    Article  PubMed  CAS  Google Scholar 

  59. 59.

    Hood KA, West LM, Northcote PT, Berridge MV, Miller JH. Induction of apoptosis by the marine sponge (Mycale) metabolites, mycalamide A and pateamine. Apoptosis. 2001;6:207–19.

    Article  PubMed  CAS  Google Scholar 

  60. 60.

    Low W-K, Li J, Zhu M, Kommaraju SS, Shah-Mittal J, Hull K, et al. Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents. Bioorg Med Chem. 2014;22:116–25.

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Chen R, Zhu M, Chaudhari RR, Robles O, Chen Y, Skillern W, et al. Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia. Leukemia. 2019.

  62. 62.

    Kuznetsov G, Xu Q, Rudolph-Owen L, TenDyke K, Liu J, Towle M, et al. Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A. Mol Cancer Ther. 2009;8:1250–60.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. 63.

    Korneeva NL, Song A, Gram H, Edens MA, Rhoads RE. Inhibition of mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) preferentially affects translation of mRNAs containing both a 5′-terminal cap and hairpin. J Biol Chem. 2016;291:3455–67.

    Article  PubMed  CAS  Google Scholar 

  64. 64.

    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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. 65.

    Joshi S, Platanias LC. Mnk kinases in cytokine signaling and regulation of cytokine responses. Biomol Concepts. 2012;3:127–39.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. 66.

    Joshi S, Platanias LC. Mnk kinase pathway: cellular functions and biological outcomes. World J Biol Chem. 2014;5:321–33.

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Reich SH, Sprengeler PA, Chiang GG, Appleman JR, Chen J, Clarine J, et al. 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. 2018;61:3516–40.

    Article  PubMed  CAS  Google Scholar 

  68. 68.

    Riner A, Chan-Tack KM, Murray JS. Original research: intravenous ribavirin--review of the FDA’s emergency investigational new drug database (1997-2008) and literature review. Postgrad Med. 2009;121:139–46.

    Article  PubMed  Google Scholar 

  69. 69.

    Borden KL, Culjkovic-Kraljacic B. Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma. 2010;51:1805–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. 70.

    Urtishak KA, Wang LS, Culjkovic-Kraljacic B, Davenport JW, Porazzi P, Vincent TL, et al. Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia. Oncogene. 2019;38:2241–62.

    Article  PubMed  CAS  Google Scholar 

  71. 71.

    Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood. 2009;114:257–60.

    Article  PubMed  CAS  Google Scholar 

  72. 72.

    Kraljacic BC, Arguello M, Amri A, Cormack G, Borden K. Inhibition of eIF4E with ribavirin cooperates with common chemotherapies in primary acute myeloid leukemia specimens. Leukemia. 2011;25:1197–200.

    Article  PubMed  CAS  Google Scholar 

  73. 73.

    Martinez-Marignac V, Shawi M, Pinedo-Carpio E, Wang X, Panasci L, Miller W, et al. Pharmacological targeting of eIF4E in primary CLL lymphocytes. Blood Cancer J. 2013;3:e146.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. 74.

    Dunn LA, Fury MG, Sherman EJ, Ho AA, Katabi N, Haque SS, et al. Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer. Head Neck. 2018;40:233–41.

    Article  PubMed  Google Scholar 

  75. 75.

    Kosaka T, Nagamatsu G, Saito S, Oya M, Suda T, Horimoto K. Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming. Cancer Sci. 2013;104:1017–26.

    Article  PubMed  CAS  Google Scholar 

  76. 76.

    Jans DA, Martin AJ, Wagstaff KM. Inhibitors of nuclear transport. Curr Opin Cell Biol. 2019;58:50–60.

    Article  PubMed  CAS  Google Scholar 

  77. 77.

    Çağatay T, Chook YM. Karyopherins in cancer. Curr Opin Cell Biol. 2018;52:30–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. 78.

    Xu D, Grishin NV, Chook YM. NESdb: a database of NES-containing CRM1 cargoes. Mol Biol Cell. 2012;23:3673–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. 79.

    Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB. eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR. J Cell Biol. 2005;169:245–56.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. 80.

    Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol. 2006;175:415–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. 81.

    Culjkovic-Kraljacic, B., Baguet, A., Volpon, L., Amri, A. & Borden, Katherine L.B. The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep 2, 207–215 (2012).

  82. 82.

    Fung HYJ, Chook YM. Atomic basis of CRM1-cargo recognition, release and inhibition. Semin Cancer Biol. 2014;27:52–61.

    Article  PubMed  CAS  Google Scholar 

  83. 83.

    Wang AY, Liu H. The past, present, and future of CRM1/XPO1 inhibitors. Stem cell investigation. 2019;6:6–6.

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Sun Q, Chen X, Zhou Q, Burstein E, Yang S, Jia D. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal transduction and targeted therapy. 2016;1:16010.

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Sun H, Hattori N, Chien W, Sun Q, Sudo M, E-Ling GL, et al. KPT-330 has antitumour activity against non-small cell lung cancer. Br J Cancer. 2014;111:281–91.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. 86.

    Gandhi UH, Senapedis W, Baloglu E, Unger TJ, Chari A, Vogl D, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18:335–45.

    Article  PubMed  Google Scholar 

  87. 87.

    Yang J, Bill MA, Young GS, la Perle K, Landesman Y, Shacham S, et al. Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. PLoS One. 2014;9:e102983.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  88. 88.

    Ranganathan P, Kashyap T, Yu X, Meng X, Lai TH, McNeil B, et al. XPO1 inhibition using selinexor synergizes with chemotherapy in acute myeloid leukemia by targeting DNA repair and restoring topoisomerase IIα to the nucleus. Clin Cancer Res. 2016;22:6142–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. 89.

    Garg M, Kanojia D, Mayakonda A, Ganesan TS, Sadhanandhan B, Suresh S, et al. Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. Sci Rep. 2017;7:9749.

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    clinicaltrials.gov. Studies found for selinexor (2019).

  91. 91.

    Garzon R, Savona M, Baz R, Andreeff M, Gabrail N, Gutierrez M, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129:3165–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  92. 92.

    Zhang W, et al. Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica. 2018;103:1642–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. 93.

    Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, et al. Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol. 2016;34:3166–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. 94.

    Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:859–66.

    Article  PubMed  CAS  Google Scholar 

  95. 95.

    Khoury HJ, Cortes J, Baccarani M, Wetzler M, Masszi T, Digumarti R, et al. Omacetaxine mepesuccinate in patients with advanced chronic myeloid leukemia with resistance or intolerance to tyrosine kinase inhibitors. Leuk Lymphoma. 2015;56:120–7.

    Article  PubMed  CAS  Google Scholar 

  96. 96.

    Quintas-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115:5382–93.

    Article  PubMed  CAS  Google Scholar 

  97. 97.

    Tujebajeva RM, Graifer DM, Karpova GG, Ajtkhozhina NA. Alkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation. FEBS Lett. 1989;257:254–6.

    Article  PubMed  CAS  Google Scholar 

  98. 98.

    Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des. 2011;17:59–64.

    Article  PubMed  CAS  Google Scholar 

  99. 99.

    Tujebajeva RM, Graifer DM, Matasova NB, Fedorova OS, Odintsov VB, Ajtkhozhina NA, et al. Selective inhibition of the polypeptide chain elongation in eukaryotic cells. Biochim Biophys Acta. 1992;1129:177–82.

    Article  PubMed  CAS  Google Scholar 

  100. 100.

    Lam SS, et al. Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia. Sci Transl Med. 2016;8:359ra129.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  101. 101.

    Liu J, Mi Y, Fu M, Yu W, Wang Y, Lin D, et al. Intensive induction chemotherapy with regimen containing intermediate dose cytarabine in the treatment of de novo acute myeloid leukemia. Am J Hematol. 2009;84:422–7.

    Article  PubMed  CAS  Google Scholar 

  102. 102.

    Jin J, Wang JX, Chen FF, Wu DP, Hu J, Zhou JF, et al. Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2013;14:599–608.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Changchun Deng.

Ethics declarations

Conflict of Interest

Ipsita Pal, Maryam Safari, Marko Jovanovic, and Susan E. Bates declare that they have no conflict of interest.

Changchun Deng reports grants from TG Therapeutics and Amgen. In addition, Dr. Deng has two patents pending related to the topic reviewed here: 15003-353US0 and IR# CU19337.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pal, I., Safari, M., Jovanovic, M. et al. Targeting Translation of mRNA as a Therapeutic Strategy in Cancer. Curr Hematol Malig Rep 14, 219–227 (2019). https://doi.org/10.1007/s11899-019-00530-y

Download citation

Keywords

  • Translation
  • Translation inhibitor
  • 4E-BP1
  • eIF4A
  • eIF4E
  • Omacetaxine
  • Umbralisib
  • Selinexor