The Role of mRNA Translational Control in Tumor Immune Escape and Immunotherapy Resistance.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 11 2021
15 11 2021
Historique:
received:
10
05
2021
revised:
19
08
2021
accepted:
31
08
2021
pubmed:
3
9
2021
medline:
11
1
2022
entrez:
2
9
2021
Statut:
ppublish
Résumé
Tremendous advances have been made in cancer immunotherapy over the last decade. Among the different steps of gene expression, translation of mRNA is emerging as an essential player in both cancer and immunity. Changes in mRNA translation are both rapid and adaptive, and translational reprogramming is known to be necessary for sustaining cancer cell proliferation. However, the role of mRNA translation in shaping an immune microenvironment permissive to tumors has not been extensively studied. Recent studies on immunotherapy approaches have indicated critical roles of mRNA translation in regulating the expression of immune checkpoint proteins, tuning the secretion of inflammation-associated factors, modulating the differentiation of immune cells in the tumor microenvironment, and promoting cancer resistance to immunotherapies. Careful consideration of the role of mRNA translation in the tumor-immune ecosystem could suggest more effective therapeutic strategies and may eventually change the current paradigm of cancer immunotherapy. In this review, we discuss recent advances in understanding the relationship between mRNA translation and tumor-associated immunity, the potential mechanisms of immunotherapy resistance in cancers linked to translational reprogramming, and therapeutic perspectives and potential challenges of modulating translational regulation in cancer immunotherapy.
Identifiants
pubmed: 34470777
pii: 0008-5472.CAN-21-1466
doi: 10.1158/0008-5472.CAN-21-1466
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
5596-5604Informations de copyright
©2021 American Association for Cancer Research.
Références
Buttgereit F, Brand MD. A hierarchy of ATP-consuming processes in mammalian cells. Biochem J. 1995;312:163–7.
Lee LJ, Papadopoli D, Jewer M, Del Rincon S, Topisirovic I, Lawrence MG, et al. Cancer plasticity: The role of mRNA translation. Trends Cancer. 2021;7:134–45.
Huang F, Goncalves C, Bartish M, Remy-Sarrazin J, Issa ME, Cordeiro B, et al. Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates anti-tumor immune responses. J Clin Invest. 2021;131:e140752.
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.
Xu Y, Ruggero D. The role of translation control in tumorigenesis and its therapeutic implications. Annual Review of Cancer Biology. 2020;4:437–57.
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.
Apcher S, Manoury B, Fahraeus R. The role of mRNA translation in direct MHC class I antigen presentation. Curr Opin Immunol. 2012;24:71–6.
Han BS, Ji S, Woo S, Lee JH, Sin JI. Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model. Sci Rep. 2019;9:2855.
Apcher S, Daskalogianni C, Lejeune F, Manoury B, Imhoos G, Heslop L, et al. Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. PNAS. 2011;108:11572–7.
Araki K, Morita M, Bederman AG, Konieczny BT, Kissick HT, Sonenberg N, et al. Translation is actively regulated during the differentiation of CD8(+) effector T cells. Nat Immunol. 2017;18:1046–57.
Ricciardi S, Manfrini N, Alfieri R, Calamita P, Crosti MC, Gallo S, et al. The translational machinery of human CD4(+) T Cells is poised for activation and controls the switch from quiescence to metabolic remodeling. Cell Metab. 2018;28:961.
Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136:731–45.
Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5′-untranslated regions of eukaryotic mRNAs. Science. 2016;352:1413–6.
Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309:1559–63.
Arrick BA, Grendell RL, Griffin LA. Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells. Mol Cell Biol. 1994;14:619–28.
Malka-Mahieu H, Newman M, Desaubry L, Robert C, Vagner S. Molecular pathways: the eIF4F translation initiation complex-new opportunities for cancer treatment. Clin Cancer Res. 2017;23:21–5.
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.
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. 2001;268:5375–85.
Scheper GC, Proud CG. Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation?. Eur J Biochem. 2002;269:5350–9.
Zuberek J, Jemielity J, Jablonowska A, Stepinski J, Dadlez M, Stolarski R, et al. Influence of electric charge variation at residues 209 and 159 on the interaction of eIF4E with the mRNA 5′ terminus. Biochemistry. 2004;43:5370–9.
Topisirovic I, Ruiz-Gutierrez M, Borden KL. Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 2004;64:8639–42.
Robichaud N, del Rincon SV, Huor B, Alain T, Petruccelli LA, Hearnden J, et al. Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene. 2015;34:2032–42.
Jennings MD, Kershaw CJ, Adomavicius T, Pavitt GD. Fail-safe control of translation initiation by dissociation of eIF2alpha phosphorylated ternary complexes. eLife. 2017;6:e24542.
Wells SE, Hillner PE, Vale RD, Sachs AB. Circularization of mRNA by eukaryotic translation initiation factors. Mol Cell. 1998;2:135–40.
Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.
Cogdill AP, Andrews MC, Wargo JA. Hallmarks of response to immune checkpoint blockade. Br J Cancer. 2017;117:1–7.
Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol. 2017;14:655–68.
Garcia-Diaz A, Shin DS, Moreno BH, Saco J, Escuin-Ordinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2017;19:1189–201.
Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018;48:434–52.
Han SJ, Ahn BJ, Waldron JS, Yang I, Fang S, Crane CA, et al. Gamma interferon-mediated superinduction of B7-H1 in PTEN-deficient glioblastoma: a paradoxical mechanism of immune evasion. Neuroreport. 2009;20:1597–602.
Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6:202–16.
Vidotto T, Melo CM, Castelli E, Koti M, Dos Reis RB, Squire JA. Emerging role of PTEN loss in evasion of the immune response to tumours. Br J Cancer. 2020;122:1732–43.
George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, et al. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity. 2017;46:197–204.
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.
Suresh S, Chen B, Zhu J, Golden RJ, Lu C, Evers BM, et al. eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer. Nat Cancer. 2020;1:533–45.
Bjur E, Larsson O, Yurchenko E, Zheng L, Gandin V, Topisirovic I, et al. Distinct translational control in CD4+ T cell subsets. PLos Genet. 2013;9:e1003494.
Davari K, Lichti J, Gallus C, Greulich F, Uhlenhaut NH, Heinig M, et al. Rapid Genome-wide Recruitment of RNA Polymerase II Drives Transcription, Splicing, and Translation Events during T Cell Responses. Cell Rep. 2017;19:643–54.
Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells. Cell Res. 2020;30:649–59.
Varanasi SK, Kumar SV, Rouse BT. Determinants of tissue-specific metabolic adaptation of T cells. Cell Metab. 2020;32:908–19.
Wei J, Zheng W, Chapman NM, Geiger TL, Chi H. T cell metabolism in homeostasis and cancer immunity. Curr Opin Biotechnol. 2021;68:240–50.
Cook KD, Miller J. TCR-dependent translational control of GATA-3 enhances Th2 differentiation. J Immunol. 2010;185:3209–16.
Gorentla BK, Krishna S, Shin J, Inoue M, Shinohara ML, Grayson JM, et al. Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2013;190:1026–37.
Murooka TT, Rahbar R, Platanias LC, Fish EN. CCL5-mediated T-cell chemotaxis involves the initiation of mRNA translation through mTOR/4E-BP1. Blood. 2008;111:4892–901.
Ben-Sahra I, Manning BD. mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol. 2017;45:72–82.
Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G, Vogel P, et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity. 2013;39:1043–56.
Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, et al. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature. 2015;517:497–500.
Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44.
Ricciardi S, Manfrini N, Alfieri R, Calamita P, Crosti MC, Gallo S, et al. The translational machinery of human CD4(+) T Cells is poised for activation and controls the switch from quiescence to metabolic remodeling. Cell Metab. 2018;28:895–906.
Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O'Sullivan D, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153:1239–51.
Mao Y, van Hoef V, Zhang X, Wennerberg E, Lorent J, Witt K, et al. IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells. Blood. 2016;128:1475–89.
Frutoso M, Morisseau S, Tamzalit F, Quemener A, Meghnem D, Leray I, et al. Emergence of NK cell hyporesponsiveness after two IL-15 stimulation cycles. J Immunol. 2018;201:493–506.
Pereno R, Giron-Michel J, Gaggero A, Cazes E, Meazza R, Monetti M, et al. IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα. Oncogene. 2000;19:5153–62.
Seike M, Yanaihara N, Bowman ED, Zanetti KA, Budhu A, Kumamoto K, et al. Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J Natl Cancer Inst. 2007;99:1257–69.
Lelouard H, Schmidt EK, Camosseto V, Clavarino G, Ceppi M, Hsu HT, et al. Regulation of translation is required for dendritic cell function and survival during activation. J Cell Biol. 2007;179:1427–39.
Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.
Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350:207–11.
Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377:2500–1.
Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21:1353–65.
Choi SH, Martinez TF, Kim S, Donaldson C, Shokhirev MN, Saghatelian A, et al. CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability. Genes Dev. 2019;33:418–35.
Yang C, Tian C, Hoffman TE, Jacobsen NK, Spencer SL. Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling. Nat Commun. 2021;12:1747.
Falletta P, Sanchez-Del-Campo L, Chauhan J, Effern M, Kenyon A, Kershaw CJ, et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev. 2017;31:18–33.
Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 2014;4:816–27.
Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun. 2014;5:5712.
Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118:9–16.
DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19:369–82.
Schott J, Reitter S, Philipp J, Haneke K, Schafer H, Stoecklin G. Translational regulation of specific mRNAs controls feedback inhibition and survival during macrophage activation. PLos Genet. 2014;10:e1004368.
Bao Y, Wu X, Chen J, Hu X, Zeng F, Cheng J, et al. Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of IkappaBalpha. PNAS. 2017;114:E3993–4001.
Su X, Yu Y, Zhong Y, Giannopoulou EG, Hu X, Liu H, et al. Interferon-gamma regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat Immunol. 2015;16:838–49.
Lopez-Pelaez M, Fumagalli S, Sanz C, Herrero C, Guerra S, Fernandez M, et al. Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages. Mol Biol Cell. 2012;23:2982–92.
Kalafati L, Mitroulis I, Verginis P, Chavakis T, Kourtzelis I. Neutrophils as orchestrators in tumor development and metastasis formation. Front Oncol. 2020;10:581457.
Lindemann SW, Yost CC, Denis MM, McIntyre TM, Weyrich AS, Zimmerman GA. Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. PNAS. 2004;101:7076–81.
Robichaud N, Hsu BE, Istomine R, Alvarez F, Blagih J, Ma EH, et al. Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils. Proc Natl Acad Sci U S A. 2018;115:E2202–E9.
Cools-Lartigue J, Spicer J, McDonald B, Gowing S, Chow S, Giannias B, et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J Clin Invest. 2013;123:3446–58.
Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76:1367–80.
Albrengues J, Shields MA, Ng D, Park CG, Ambrico A, Poindexter ME, et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science. 2018;361:eaao4227.
Teijeira A, Garasa S, Gato M, Alfaro C, Migueliz I, Cirella A, et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity. 2020;52:856–71.
Ireland AS, Oliver TG. Neutrophils create an ImpeNETrable shield between tumor and cytotoxic immune cells. Immunity. 2020;52:729–31.
McInturff AM, Cody MJ, Elliott EA, Glenn JW, Rowley JW, Rondina MT, et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Blood. 2012;120:3118–25.
Dumont FJ, Su Q. Mechanism of action of the immunosuppressant rapamycin. Life Sci. 1996;58:373–95.
Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. PNAS. 2008;105:17414–9.
So L, Lee J, Palafox M, Mallya S, Woxland CG, Arguello M, et al. The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes. Sci Signal. 2016;9:ra57.
Chaoul N, Fayolle C, Desrues B, Oberkampf M, Tang A, Ladant D, et al. Rapamycin impairs antitumor CD8+ T-cell responses and vaccine-induced tumor eradication. Cancer Res. 2015;75:3279–91.
Beziaud L, Boullerot L, Tran T, Mansi L, EL M-J, Ravel P, et al. Rapalog combined with CCR4 antagonist improves anticancer vaccines efficacy. Int J Cancer. 2018;143:3008–18.
Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108–12.
Li Q, Rao R, Vazzana J, Goedegebuure P, Odunsi K, Gillanders W, et al. Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity. J Immunol. 2012;188:3080–7.
Wang Y, Wang XY, Subjeck JR, Shrikant PA, Kim HL. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br J Cancer. 2011;104:643–52.
Berezhnoy A, Castro I, Levay A, Malek TR, Gilboa E. Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity. J Clin Invest. 2014;124:188–97.
Wendel HG, Silva RL, Malina A, Mills JR, Zhu H, Ueda T, et al. Dissecting eIF4E action in tumorigenesis. Genes Dev. 2007;21:3232–7.
Cao J, Sun X, Zhang X, Chen D. Inhibition of eIF4E cooperates with chemotherapy and immunotherapy in renal cell carcinoma. Clin Transl Oncol. 2018;20:761–7.
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.
Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–7.
Boshuizen J, Vredevoogd DW, Krijgsman O, Ligtenberg MA, Blankenstein S, de Bruijn B, et al. Reversal of pre-existing NGFR-driven tumor and immune therapy resistance. Nat Commun. 2020;11:3946.
Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118:2651–60.
Et C, Koppel K. Associations of volatile compounds with sensory aroma and flavor: the complex nature of flavor. Molecules. 2013;18:4887–905.
Sadlish H, Galicia-Vazquez G, Paris CG, Aust T, Bhullar B, Chang L, et al. Evidence for a functionally relevant rocaglamide binding site on the eIF4A-RNA complex. ACS Chem Biol. 2013;8:1519–27.
Bordeleau ME, Cencic R, Lindqvist L, Oberer M, Northcote P, Wagner G, et al. RNA-mediated sequestration of the RNA helicase eIF4A by Pateamine A inhibits translation initiation. Chem Biol. 2006;13:1287–95.
Lindqvist L, Oberer M, Reibarkh M, Cencic R, Bordeleau ME, Vogt E, et al. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS One. 2008;3:e1583.
Bordeleau ME, Matthews J, Wojnar JM, Lindqvist L, Novac O, Jankowsky E, et al. Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation. Proc Natl Acad Sci U S A. 2005;102:10460–5.
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.
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.
Thuaud F, Bernard Y, Turkeri G, Dirr R, Aubert G, Cresteil T, et al. Synthetic analogue of rocaglaol displays a potent and selective cytotoxicity in cancer cells: involvement of apoptosis inducing factor and caspase-12. J Med Chem. 2009;52:5176–87.
Ernst JT, Thompson PA, Nilewski C, Sprengeler PA, Sperry S, Packard G, et al. Design of development candidate eFT226, a First in class inhibitor of eukaryotic initiation factor 4A RNA Helicase. J Med Chem. 2020;63:5879–955.
Thompson PA, Eam B, Young NP, Fish S, Chen J, Barrera M, et al. Targeting oncogene mRNA translation in B-cell malignancies with eFT226, a potent and selective inhibitor of eIF4A. Mol Cancer Ther. 2021;20:26–36.