Skip to main content
SpringerLink
Log in

Targeting XPO1-Dependent Nuclear Export in Cancer

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Nucleocytoplasmic transport of macromolecules is tightly regulated in eukaryotic cells. XPO1 is a transport factor responsible for the nuclear export of several hundred protein and RNA substrates. Elevated levels of XPO1 and recurrent mutations have been reported in multiple cancers and linked to advanced disease stage and poor survival. In recent years, several novel small-molecule inhibitors of XPO1 were developed and extensively tested in preclinical cancer models and eventually in clinical trials. In this brief review, we summarize the functions of XPO1, its role in cancer, and the latest results of clinical trials of XPO1 inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AML:

acute myeloid leukemia

CLL:

chronic lymphocytic leukemia

CR:

complete response

DLBCL:

diffuse large B-cell lymphoma

MCL:

mantle cell lymphoma

MM:

multiple myeloma

NES:

nuclear export signal

R/R:

relapsed or refractory

References

  1. Beck, M., and Hurt, E. (2017) The nuclear pore complex: understanding its function through structural insight, Nat. Rev. Mol. Cell Biol., 18, 73-89, https://doi.org/10.1038/nrm.2016.147.

    Article  CAS  PubMed  Google Scholar 

  2. Timney, B. L., Raveh, B., Mironska, R., Trivedi, J. M., Kim, S. J., et al. (2016) Simple rules for passive diffusion through the nuclear pore complex, J. Cell Biol., 215, 57-76, https://doi.org/10.1083/jcb.201601004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cagatay, T., and Chook, Y. M. (2018) Karyopherins in cancer, Curr. Opin. Cell. Biol., 52, 30-42, https://doi.org/10.1016/j.ceb.2018.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sorokin, A. V., Kim, E. R., and Ovchinnikov, L. P. (2007) Nucleocytoplasmic transport of proteins, Biochemistry (Moscow), 72, 1439-1457, https://doi.org/10.1134/s0006297907130032.

    Article  CAS  Google Scholar 

  5. Adachi, Y., and Yanagida, M. (1989) Higher order chromosome structure is affected by cold-sensitive mutations in a Schizosaccharomyces pombe gene crm1+ which encodes a 115-kDa protein preferentially localized in the nucleus and its periphery, J. Cell Biol., 108, 1195-1207, https://doi.org/10.1083/jcb.108.4.1195.

    Article  CAS  PubMed  Google Scholar 

  6. Fornerod, M., Ohno, M., Yoshida, M., and Mattaj, I. W. (1997) CRM1 is an export receptor for leucine-rich nuclear export signals, Cell, 90, 1051-1060, https://doi.org/10.1016/s0092-8674(00)80371-2.

    Article  CAS  PubMed  Google Scholar 

  7. Fukuda, M., Asano, S., Nakamura, T., Adachi, M., Yoshida, M., et al. (1997) CRM1 is responsible for intracellular transport mediated by the nuclear export signal, Nature, 390, 308-311, https://doi.org/10.1038/36894.

    Article  CAS  PubMed  Google Scholar 

  8. Ossareh-Nazari, B., Bachelerie, F., and Dargemont, C. (1997) Evidence for a role of CRM1 in signal-mediated nuclear protein export, Science, 278, 141-144, https://doi.org/10.1126/science.278.5335.141.

    Article  CAS  PubMed  Google Scholar 

  9. Stade, K., Ford, C. S., Guthrie, C., and Weis, K. (1997) Exportin 1 (Crm1p) is an essential nuclear export factor, Cell, 90, 1041-1050, https://doi.org/10.1016/s0092-8674(00)80370-0.

    Article  CAS  PubMed  Google Scholar 

  10. Lee, Y., Pei, J., Baumhardt, J. M., Chook, Y. M., and Grishin, N. V. (2019) Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site, Sci. Rep., 9, 6627, https://doi.org/10.1038/s41598-019-43004-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fung, H. Y., Fu, S. C., Brautigam, C. A., and Chook, Y. M. (2015) Structural determinants of nuclear export signal orientation in binding to exportin CRM1, Elife, 4, e10034, https://doi.org/10.7554/eLife.10034.

    Article  PubMed Central  Google Scholar 

  12. Kosugi, S., Hasebe, M., Tomita, M., and Yanagawa, H. (2008) Nuclear export signal consensus sequences defined using a localization-based yeast selection system, Traffic, 9, 2053-2062, https://doi.org/10.1111/j.1600-0854.2008.00825.x.

    Article  CAS  PubMed  Google Scholar 

  13. Hutten, S., and Kehlenbach, R. H. (2007) CRM1-mediated nuclear export: to the pore and beyond, Trends Cell Biol., 17, 193-201, https://doi.org/10.1016/j.tcb.2007.02.003.

    Article  CAS  PubMed  Google Scholar 

  14. Fu, S. C., Huang, H. C., Horton, P., and Juan, H. F. (2013) ValidNESs: a database of validated leucine-rich nuclear export signals, Nucleic Acids Res., 41, D338-D343, https://doi.org/10.1093/nar/gks936.

    Article  CAS  PubMed  Google Scholar 

  15. Xu, D., Grishin, N. V., and Chook, Y. M. (2012) NESdb: a database of NES-containing CRM1 cargoes, Mol.Biol. Cell, 23, 3673-3676, https://doi.org/10.1091/mbc.E12-01-0045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Thakar, K., Karaca, S., Port, S. A., Urlaub, H., and Kehlenbach, R. H. (2013) Identification of CRM1-dependent nuclear export cargos using quantitative mass spectrometry, Mol. Cell. Proteomics, 12, 664-678, https://doi.org/10.1074/mcp.M112.024877.

    Article  CAS  PubMed  Google Scholar 

  17. Kirli, K., Karaca, S., Dehne, H. J., Samwer, M., Pan, K. T., et al. (2015) A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning, Elife, 4, e11466, https://doi.org/10.7554/eLife.11466.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wuhr, M., Guttler, T., Peshkin, L., McAlister, G. C., Sonnett, M., et al. (2015) The nuclear proteome of a vertebrate, Curr. Biol., 25, 2663-2671, https://doi.org/10.1016/j.cub.2015.08.047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mackmull, M. T., Klaus, B., Heinze, I., Chokkalingam, M., Beyer, A., et al. (2017) Landscape of nuclear transport receptor cargo specificity, Mol. Syst. Biol., 13, 962, https://doi.org/10.15252/msb.20177608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hill, R., Cautain, B., de Pedro, N., and Link, W. (2014) Targeting nucleocytoplasmic transport in cancer therapy, Oncotarget, 5, 11-28, https://doi.org/10.18632/oncotarget.1457.

    Article  PubMed  Google Scholar 

  21. Johnson, A. W., Lund, E., and Dahlberg, J. (2002) Nuclear export of ribosomal subunits, Trends Biochem. Sci., 27, 580-585, https://doi.org/10.1016/s0968-0004(02)02208-9.

    Article  CAS  PubMed  Google Scholar 

  22. Wild, T., Horvath, P., Wyler, E., Widmann, B., Badertscher, L., Zemp, I., et al. (2010) A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export, PLoS Biol., 8, e1000522, https://doi.org/10.1371/journal.pbio.1000522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Muqbil, I., Bao, B., Abou-Samra, A. B., Mohammad, R. M., and Azmi, A. S. (2013) Nuclear export mediated regulation of microRNAs: potential target for drug intervention, Curr. Drug Targets, 14, 1094-1100, https://doi.org/10.2174/1389450111314100002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Volpon, L., Culjkovic-Kraljacic, B., Sohn, H. S., Blanchet-Cohen, A., Osborne, M. J., et al. (2017) A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery, RNA, 23, 927-937, https://doi.org/10.1261/rna.060137.116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Topisirovic, I., Siddiqui, N., Lapointe, V. L., Trost, M., Thibault, P., et al. (2009) Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP, EMBO J., 28, 1087-1098, https://doi.org/10.1038/emboj.2009.53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ohno, M., Segref, A., Bachi, A., Wilm, M., and Mattaj, I. W. (2000) PHAX, a mediator of U snRNA nuclear export whose activity is regulated by phosphorylation, Cell, 101, 187-198, https://doi.org/10.1016/S0092-8674(00)80829-6.

    Article  CAS  PubMed  Google Scholar 

  27. Izaurralde, E., Lewis, J., Gamberi, C., Jarmolowski, A., McGuigan, C., et al. (1995) A cap-binding protein complex mediating U snRNA export, Nature, 376, 709-712, https://doi.org/10.1038/376709a0.

    Article  CAS  PubMed  Google Scholar 

  28. Forbes, D. J., Travesa, A., Nord, M. S., and Bernis, C. (2015) Nuclear transport factors: Global regulation of mitosis, Curr. Opin. Cell Biol., 35, 78-90, https://doi.org/10.1016/j.ceb.2015.04.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yao, Y., Dong, Y., Lin, F., Zhao, H., Shen, Z., et al. (2009) The expression of CRM1 is associated with prognosis in human osteosarcoma, Oncol. Rep., 21, 229-235, https://doi.org/10.3892/or_00000213.

    Article  CAS  PubMed  Google Scholar 

  30. Noske, A., Weichert, W., Niesporek, S., Roske, A., Buckendahl, A. C., et al. (2008) Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer, Cancer, 112, 1733-1743, https://doi.org/10.1002/cncr.23354.

    Article  CAS  PubMed  Google Scholar 

  31. Huang, W. Y., Yue, L., Qiu, W. S., Wang, L. W., Zhou, X. H., et al. (2009) Prognostic value of CRM1 in pancreas cancer, Clin. Invest. Med., 32, E315.

    Article  PubMed  Google Scholar 

  32. Shen, A., Wang, Y., Zhao, Y., Zou, L., Sun, L., et al. (2009) Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis, Neurosurgery, 65, 153-160, https://doi.org/10.1227/01.NEU.0000348550.47441.4B.

    Article  PubMed  Google Scholar 

  33. Van der Watt, P. J., Maske, C. P., Hendricks, D. T., Parker, M. I., Denny, L., et al. (2009) The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation, Int. J. Cancer, 124, 1829-1840, https://doi.org/10.1002/ijc.24146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sexton, R., Mahdi, Z., Chaudhury, R., Beydoun, R., Aboukameel, A., et al. (2019) Targeting nuclear exporter protein XPO1/CRM1 in gastric cancer, Int. J. Mol. Sci., 20, 4826, https://doi.org/10.3390/ijms20194826.

    Article  CAS  PubMed Central  Google Scholar 

  35. Zhou, F., Qiu, W., Yao, R., Xiang, J., Sun, X., et al. (2013) CRM1 is a novel independent prognostic factor for the poor prognosis of gastric carcinomas, Med. Oncol., 30, 726, https://doi.org/10.1007/s12032-013-0726-1.

    Article  CAS  PubMed  Google Scholar 

  36. Inoue, H., Kauffman, M., Shacham, S., Landesman, Y., Yang, J., et al. (2013) CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth, J. Urol., 189, 2317-2326, https://doi.org/10.1016/j.juro.2012.10.018.

    Article  CAS  PubMed  Google Scholar 

  37. Van der Watt, P. J., Zemanay, W., Govender, D., Hendricks, D. T., Parker, M. I., et al. (2014) Elevated expression of the nuclear export protein, Crm1 (exportin 1), associates with human oesophageal squamous cell carcinoma, Oncol. Rep., 32, 730-738, https://doi.org/10.3892/or.2014.3231.

    Article  PubMed  Google Scholar 

  38. Zheng, Y., Gery, S., Sun, H., Shacham, S., Kauffman, M., et al. (2014) KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma, Cancer Chemother. Pharmacol., 74, 487-495, https://doi.org/10.1007/s00280-014-2495-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kojima, K., Kornblau, S. M., Ruvolo, V., Dilip, A., Duvvuri, S., et al. (2013) Prognostic impact and targeting of CRM1 in acute myeloid leukemia, Blood, 121, 4166-4174, https://doi.org/10.1182/blood-2012-08-447581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lapalombella, R., Sun, Q., Williams, K., Tangeman, L., Jha, S., Zhong, Y., et al. (2012) Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia, Blood, 120, 4621-4634, https://doi.org/10.1182/blood-2012-05-429506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yoshimura, M., Ishizawa, J., Ruvolo, V., Dilip, A., Quintas-Cardama, A., et al. (2014) Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma, Cancer Sci., 105, 795-801, https://doi.org/10.1111/cas.12430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, K., Wang, M., Tamayo, A. T., Shacham, S., Kauffman, M., et al. (2013) Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma, Exp. Hematol., 41, 67-78.e64, https://doi.org/10.1016/j.exphem.2012.09.002.

    Article  CAS  PubMed  Google Scholar 

  43. Schmidt, J., Braggio, E., Kortuem, K. M., Egan, J. B., Zhu, Y. X., et al. (2013) Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276, Leukemia, 27, 2357-2365, https://doi.org/10.1038/leu.2013.172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tai, Y. T., Landesman, Y., Acharya, C., Calle, Y., Zhong, M. Y., et al. (2014) CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications, Leukemia, 28, 155-165, https://doi.org/10.1038/leu.2013.115.

    Article  CAS  PubMed  Google Scholar 

  45. Luo, B., Huang, L., Gu, Y., Li, C., Lu, H., et al. (2018) Expression of exportin-1 in diffuse large B-cell lymphoma: Immunohistochemistry and TCGA analyses, Int. J. Clin. Exp. Pathol., 11, 5547-5560.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Aladhraei, M., Kassem Al-Thobhani, A., Poungvarin, N., and Suwannalert, P. (2019) Association of XPO1 overexpression with NF-kappaB and Ki67 in colorectal cancer, Asian Pac. J. Cancer Prev., 20, 3747-3754, https://doi.org/10.31557/APJCP.2019.20.12.3747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Walker, C. J., Oaks, J. J., Santhanam, R., Neviani, P., Harb, J. G., et al. (2013) Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias, Blood, 122, 3034-3044, https://doi.org/10.1182/blood-2013-04-495374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang, J., Bill, M. A., Young, G. S., La Perle, K., Landesman, Y., et al. (2014) Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells, PLoS One, 9, e102983, https://doi.org/10.1371/journal.pone.0102983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gravina, G. L., Mancini, A., Sanita, P., Vitale, F., Marampon, F., et al. (2015) KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models, BMC Cancer, 15, 941, https://doi.org/10.1186/s12885-015-1936-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Deng, M., Zhang, M., Xu-Monette, Z. Y., Pham, L. V., Tzankov, A., et al. (2020) XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53, J. Hematol. Oncol., 13, 148, https://doi.org/10.1186/s13045-020-00982-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Galinski, B., Luxemburg, M., Landesman, Y., Pawel, B., Johnson, K. J., et al. (2021) XPO1 inhibition with selinexor synergizes with proteasome inhibition in neuroblastoma by targeting nuclear export of IkB, Transl. Oncol., 14, 101114, https://doi.org/10.1016/j.tranon.2021.101114.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Chen, Y., Camacho, S. C., Silvers, T. R., Razak, A. R., Gabrail, N. Y., et al. (2017) Inhibition of the nuclear export receptor XPO1 as a therapeutic target for platinum-resistant ovarian cancer, Clin. Cancer Res., 23, 1552-1563, https://doi.org/10.1158/1078-0432.CCR-16-1333.

    Article  CAS  PubMed  Google Scholar 

  53. Turner, J. G., Kashyap, T., Dawson, J. L., Gomez, J., Bauer, A. A., et al. (2016) XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IkappaBalpha and overcomes acquired proteasome inhibitor resistance in human multiple myeloma, Oncotarget, 7, 78896-78909, https://doi.org/10.18632/oncotarget.12969.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Turner, J. G., Dawson, J. L., Grant, S., Shain, K. H., Dalton, W. S., et al. (2016) Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors, J. Hematol. Oncol., 9, 73, https://doi.org/10.1186/s13045-016-0304-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cosson, A., Chapiro, E., Bougacha, N., Lambert, J., Herbi, L., et al. (2017) Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: Analysis of the central role of XPO1, Leukemia, 31, 1625-1629, https://doi.org/10.1038/leu.2017.100.

    Article  CAS  PubMed  Google Scholar 

  56. Chanukuppa, V., Paul, D., Taunk, K., Chatterjee, T., Sharma, S., et al. (2019) XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach, J. Proteomics, 209, 103504, https://doi.org/10.1016/j.jprot.2019.103504.

    Article  CAS  PubMed  Google Scholar 

  57. Kulkoyluoglu-Cotul, E., Smith, B. P., Wrobel, K., Zhao, Y. C., Chen, K. L. A., et al. (2019) Combined targeting of estrogen receptor alpha and XPO1 prevent Akt activation, remodel metabolic pathways and induce autophagy to overcome tamoxifen resistance, Cancers (Basel), 11, 479, https://doi.org/10.3390/cancers11040479.

    Article  CAS  Google Scholar 

  58. Jardin, F., Pujals, A., Pelletier, L., Bohers, E., Camus, V., et al. (2016) Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma, Am. J. Hematol., 91, 923-930, https://doi.org/10.1002/ajh.24451.

    Article  CAS  PubMed  Google Scholar 

  59. Mehmood, R., Jibiki, K., Shibazaki, N., and Yasuhara, N. (2021) Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer, Heliyon, 7, e06039, https://doi.org/10.1016/j.heliyon.2021.e06039.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Dong, Y., Tu, R., Liu, H., and Qing, G. (2020) Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat, Signal. Transduct. Target Ther., 5, 124, https://doi.org/10.1038/s41392-020-00235-2.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Golomb, L., Bublik, D. R., Wilder, S., Nevo, R., Kiss, V., et al. (2012) Importin 7 and exportin 1 link c-Myc and p53 to regulation of ribosomal biogenesis, Mol. Cell, 45, 222-232, https://doi.org/10.1016/j.molcel.2011.11.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., et al. (2013) Mutational landscape and significance across 12 major cancer types, Nature, 502, 333-339, https://doi.org/10.1038/nature12634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Taylor, J., Sendino, M., Gorelick, A. N., Pastore, A., Chang, M. T., et al. (2019) Altered nuclear export signal recognition as a driver of oncogenesis, Cancer Discov., 9, 1452-1467, https://doi.org/10.1158/2159-8290.CD-19-0298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jain, P., Kanagal-Shamanna, R., Wierda, W., Keating, M., Sarwari, N., et al. (2016) Clinical and molecular characteristics of XPO1 mutations in patients with chronic lymphocytic leukemia, Am. J. Hematol., 91, E478-E479, https://doi.org/10.1002/ajh.24496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Puente, X. S., Pinyol, M., Quesada, V., Conde, L., Ordonez, G. R., et al. (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia, Nature, 475, 101-105, https://doi.org/10.1038/nature10113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Landau, D. A., Carter, S. L., Stojanov, P., McKenna, A., Stevenson, K., et al. (2013) Evolution and impact of subclonal mutations in chronic lymphocytic leukemia, Cell, 152, 714-726, https://doi.org/10.1016/j.cell.2013.01.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Baumhardt, J. M., Walker, J. S., Lee, Y., Shakya, B., Brautigam, C. A., et al. (2020) Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation, Mol. Biol. Cell, 31, 1879-1891, https://doi.org/10.1091/mbc.E20-04-0233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Garcia-Santisteban, I., Arregi, I., Alonso-Marino, M., Urbaneja, M. A., Garcia-Vallejo, J. J., et al. (2016) A cellular reporter to evaluate CRM1 nuclear export activity: Functional analysis of the cancer-related mutant E571K, Cell. Mol. Life Sci., 73, 4685-4699, https://doi.org/10.1007/s00018-016-2292-0.

    Article  CAS  PubMed  Google Scholar 

  69. Miloudi, H., Bohers, E., Guillonneau, F., Taly, A., Gibouin, V. C., et al. (2020) XPO1(E571K) mutation modifies exportin 1 localisation and Interactome in B-cell lymphoma, Cancers (Basel), 12, 2829, https://doi.org/10.3390/cancers12102829.

    Article  CAS  Google Scholar 

  70. Gao, W., Lu, C., Chen, L., and Keohavong, P. (2015) Overexpression of CRM1: A characteristic feature in a transformed phenotype of lung carcinogenesis and a molecular target for lung cancer adjuvant therapy, J. Thorac. Oncol., 10, 815-825, https://doi.org/10.1097/JTO.0000000000000485.

    Article  CAS  PubMed  Google Scholar 

  71. Tiedemann, R. E., Zhu, Y. X., Schmidt, J., Shi, C. X., Sereduk, C., et al. (2012) Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome, Cancer Res., 72, 757-768, https://doi.org/10.1158/0008-5472.CAN-11-2781.

    Article  CAS  PubMed  Google Scholar 

  72. Hong, A. L., Tseng, Y. Y., Cowley, G. S., Jonas, O., Cheah, J. H., et al. (2016) Integrated genetic and pharmacologic interrogation of rare cancers, Nat. Commun., 7, 11987, https://doi.org/10.1038/ncomms11987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kim, J., McMillan, E., Kim, H. S., Venkateswaran, N., Makkar, G., et al. (2016) XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer, Nature, 538, 114-117, https://doi.org/10.1038/nature19771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Reddy, A., Zhang, J., Davis, N. S., Moffitt, A. B., Love, C. L., et al. (2017) Genetic and functional drivers of diffuse large B cell lymphoma, Cell, 171, 481-494.e415, https://doi.org/10.1016/j.cell.2017.09.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Inoue, A., Robinson, F. S., Minelli, R., Tomihara, H., Rizi, B. S., et al. (2021) Sequential administration of XPO1 and ATR inhibitors enhances therapeutic response in TP53-mutated colorectal cancer, Gastroenterology, 161, 196-210, https://doi.org/10.1053/j.gastro.2021.03.022.

    Article  CAS  PubMed  Google Scholar 

  76. Dickmanns, A., Monecke, T., and Ficner, R. (2015) Structural basis of targeting the exportin CRM1 in cancer, Cells, 4, 538-568, https://doi.org/10.3390/cells4030538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gravina, G. L., Senapedis, W., McCauley, D., Baloglu, E., Shacham, S., et al. (2014) Nucleo-cytoplasmic transport as a therapeutic target of cancer, J. Hematol. Oncol., 7, 85, https://doi.org/10.1186/s13045-014-0085-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Freedman, D. A., and Levine, A. J. (1998) Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6, Mol. Cell Biol., 18, 7288-7293, https://doi.org/10.1128/MCB.18.12.7288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Subhash, V. V., Yeo, M. S., Wang, L., Tan, S. H., Wong, F. Y., et al. (2018) Anti-tumor efficacy of Selinexor (KPT-330) in gastric cancer is dependent on nuclear accumulation of p53 tumor suppressor, Sci. Rep., 8, 12248, https://doi.org/10.1038/s41598-018-30686-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Boons, E., Nogueira, T. C., Dierckx, T., Menezes, S. M., Jacquemyn, M., et al. (2021) XPO1 inhibitors represent a novel therapeutic option in adult T-cell leukemia, triggering p53-mediated caspase-dependent apoptosis, Blood Cancer J., 11, 27, https://doi.org/10.1038/s41408-021-00409-3.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Stommel, J. M., Marchenko, N. D., Jimenez, G. S., Moll, U. M., Hope, T. J., et al. (1999) A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking, EMBO J., 18, 1660-1672, https://doi.org/10.1093/emboj/18.6.1660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Foo, R. S., Nam, Y. J., Ostreicher, M. J., Metzl, M. D., Whelan, R. S., et al. (2007) Regulation of p53 tetramerization and nuclear export by ARC, Proc. Natl. Acad. Sci. USA, 104, 20826-20831, https://doi.org/10.1073/pnas.0710017104.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Azmi, A. S., Al-Katib, A., Aboukameel, A., McCauley, D., Kauffman, M., et al. (2013) Selective inhibitors of nuclear export for the treatment of non-Hodgkin’s lymphomas, Haematologica, 98, 1098-1106, https://doi.org/10.3324/haematol.2012.074781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Azmi, A. S., Aboukameel, A., Bao, B., Sarkar, F. H., Philip, P. A., et al. (2013) Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice, Gastroenterology, 144, 447-456, https://doi.org/10.1053/j.gastro.2012.10.036.

    Article  CAS  PubMed  Google Scholar 

  85. Nakayama, R., Zhang, Y. X., Czaplinski, J. T., Anatone, A. J., Sicinska, E. T., et al. (2016) Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma, Oncotarget, 7, 16581-16592, https://doi.org/10.18632/oncotarget.7667.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Miyake, T., Pradeep, S., Wu, S. Y., Rupaimoole, R., Zand, B., et al. (2015) XPO1/CRM1 inhibition causes antitumor effects by mitochondrial accumulation of eIF5A, Clin. Cancer Res., 21, 3286-3297, https://doi.org/10.1158/1078-0432.CCR-14-1953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kashyap, T., Argueta, C., Aboukameel, A., Unger, T. J., Klebanov, B., et al. (2016) Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-kappaB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death, Oncotarget, 7, 78883-78895, https://doi.org/10.18632/oncotarget.12428.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Nair, J. S., Musi, E., and Schwartz, G. K. (2017) Selinexor (KPT-330) induces tumor suppression through nuclear sequestration of IkappaB and downregulation of survivin, Clin. Cancer Res., 23, 4301-4311, https://doi.org/10.1158/1078-0432.CCR-16-2632.

    Article  CAS  PubMed  Google Scholar 

  89. Han, X., Wang, J., Shen, Y., Zhang, N., Wang, S., et al. (2015) CRM1 as a new therapeutic target for non-Hodgkin lymphoma, Leuk. Res., 39, 38-46, https://doi.org/10.1016/j.leukres.2014.10.003.

    Article  CAS  PubMed  Google Scholar 

  90. Ahmed, M. M., Sheldon, D., Fruitwala, M. A., Venkatasubbarao, K., Lee, E. Y., et al. (2008) Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation, Int. J. Cancer, 122, 63-70, https://doi.org/10.1002/ijc.23019.

    Article  CAS  PubMed  Google Scholar 

  91. Azmi, A. S., Wang, Z., Burikhanov, R., Rangnekar, V. M., Wang, G., et al. (2008) Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis, Mol. Cancer Ther., 7, 2884-2893, https://doi.org/10.1158/1535-7163.MCT-08-0438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Tabe, Y., Kojima, K., Yamamoto, S., Sekihara, K., Matsushita, H., et al. (2015) Ribosomal biogenesis and translational flux inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist KPT-185, PLoS One, 10, e0137210, https://doi.org/10.1371/journal.pone.0137210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hamamoto, T., Seto, H., and Beppu, T. (1983) Leptomycins A and B, new antifungal antibiotics. II. Structure elucidation, J. Antibiot. (Tokyo), 36, 646-650, https://doi.org/10.7164/antibiotics.36.646.

    Article  CAS  Google Scholar 

  94. Nishi, K., Yoshida, M., Fujiwara, D., Nishikawa, M., Horinouchi, S., et al. (1994) Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression, J. Biol. Chem., 269, 6320-6324.

    Article  CAS  PubMed  Google Scholar 

  95. Kudo, N., Matsumori, N., Taoka, H., Fujiwara, D., Schreiner, E. P., et al. (1999) Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region, Proc. Natl. Acad. Sci. USA, 96, 9112-9117, https://doi.org/10.1073/pnas.96.16.9112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sun, Q., Carrasco, Y. P., Hu, Y., Guo, X., Mirzaei, H., et al. (2013) Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1, Proc. Natl. Acad. Sci. USA, 110, 1303-1308, https://doi.org/10.1073/pnas.1217203110.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Leopold, W. R., Shillis, J. L., Mertus, A. E., Nelson, J. M., Roberts, B. J., et al. (1984) Anticancer activity of the structurally novel antibiotic Cl-920 and its analogues, Cancer Res., 44, 1928-1932.

    CAS  PubMed  Google Scholar 

  98. Newlands, E. S., Rustin, G. J., and Brampton, M. H. (1996) Phase I trial of elactocin, Br. J. Cancer, 74, 648-649, https://doi.org/10.1038/bjc.1996.415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ferreira, B. I., Cautain, B., Grenho, I., and Link, W. (2020) Small Molecule Inhibitors of CRM1, Front. Pharmacol., 11, 625, https://doi.org/10.3389/fphar.2020.00625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kalid, O., Toledo Warshaviak, D., Shechter, S., Sherman, W., and Shacham, S. (2012) Consensus Induced Fit Docking (cIFD): Methodology, validation, and application to the discovery of novel Crm1 inhibitors, J. Comput. Aided Mol. Des., 26, 1217-1228, https://doi.org/10.1007/s10822-012-9611-9.

    Article  CAS  PubMed  Google Scholar 

  101. Parikh, K., Cang, S., Sekhri, A., and Liu, D. (2014) Selective inhibitors of nuclear export (SINE) – a novel class of anti-cancer agents, J. Hematol. Oncol., 7, 78, https://doi.org/10.1186/s13045-014-0078-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Etchin, J., Sun, Q., Kentsis, A., Farmer, A., Zhang, Z. C., et al. (2013) Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells, Leukemia, 27, 66-74, https://doi.org/10.1038/leu.2012.219.

    Article  CAS  PubMed  Google Scholar 

  103. Ranganathan, P., Yu, X., Na, C., Santhanam, R., Shacham, S., et al. (2012) Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia, Blood, 120, 1765-1773, https://doi.org/10.1182/blood-2012-04-423160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Etchin, J., Sanda, T., Mansour, M. R., Kentsis, A., Montero, J., et al. (2013) KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia, Br. J. Haematol., 161, 117-127, https://doi.org/10.1111/bjh.12231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Etchin, J., Berezovskaya, A., Conway, A. S., Galinsky, I. A., Stone, R. M., et al. (2017) KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells, Leukemia, 31, 143-150, https://doi.org/10.1038/leu.2016.145.

    Article  CAS  PubMed  Google Scholar 

  106. Hing, Z. A., Fung, H. Y., Ranganathan, P., Mitchell, S., El-Gamal, D., et al. (2016) Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies, Leukemia, 30, 2364-2372, https://doi.org/10.1038/leu.2016.136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cheng, Y., Holloway, M. P., Nguyen, K., McCauley, D., Landesman, Y., et al. (2014) XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer, Mol. Cancer Ther., 13, 675-686, https://doi.org/10.1158/1535-7163.MCT-13-0416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hing, Z. A., Mantel, R., Beckwith, K. A., Guinn, D., Williams, E., et al. (2015) Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia, Blood, 125, 3128-3132, https://doi.org/10.1182/blood-2015-01-621391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Green, A. L., Ramkissoon, S. H., McCauley, D., Jones, K., Perry, J. A., et al. (2015) Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma, Neuro Oncol., 17, 697-707, https://doi.org/10.1093/neuonc/nou303.

    Article  CAS  PubMed  Google Scholar 

  110. Wahba, A., Rath, B. H., O’Neill, J. W., Camphausen, K., and Tofilon, P. J. (2018) The XPO1 inhibitor selinexor inhibits translation and enhances the radiosensitivity of glioblastoma cells grown in vitro and in vivo, Mol. Cancer Ther., 17, 1717-1726, https://doi.org/10.1158/1535-7163.MCT-17-1303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Azmi, A. S., Khan, H. Y., Muqbil, I., Aboukameel, A., Neggers, J. E., et al. (2020) Preclinical assessment with clinical validation of selinexor with gemcitabine and Nab-paclitaxel for the treatment of pancreatic ductal adenocarcinoma, Clin. Cancer Res., 26, 1338-1348, https://doi.org/10.1158/1078-0432.CCR-19-1728.

    Article  CAS  PubMed  Google Scholar 

  112. Gravina, G. L., Mancini, A., Colapietro, A., Marampon, F., Sferra, R., et al. (2017) Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer, Oncotarget, 8, 111225-111245, https://doi.org/10.18632/oncotarget.22760.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Alexander, T. B., Lacayo, N. J., Choi, J. K., Ribeiro, R. C., Pui, C. H., et al. (2016) Phase I study of selinexor, a selective inhibitor of nuclear export, in combination with fludarabine and cytarabine, in pediatric relapsed or refractory acute leukemia, J. Clin. Oncol., 34, 4094-4101, https://doi.org/10.1200/JCO.2016.67.5066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Garzon, R., Savona, M., Baz, R., Andreeff, M., Gabrail, N., et al. (2017) A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia, Blood, 129, 3165-3174, https://doi.org/10.1182/blood-2016-11-750158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang, A. Y., Weiner, H., Green, M., Chang, H., Fulton, N., et al. (2018) A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia, J. Hematol. Oncol., 11, 4, https://doi.org/10.1186/s13045-017-0550-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, W., Ly, C., Ishizawa, J., Mu, H., Ruvolo, V., et al. (2018) 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, 103, 1642-1653, https://doi.org/10.3324/haematol.2017.185082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Abboud, R., Chendamarai, E., Rettig, M. P., Trinkaus, K. M., Riedell, P. A., et al. (2020) Selinexor combined with cladribine, cytarabine, and filgrastim in relapsed or refractory acute myeloid leukemia, Haematologica, 105, e404-e407, https://doi.org/10.3324/haematol.2019.236810.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Sweet, K., Komrokji, R., Padron, E., Cubitt, C. L., Turner, J. G., et al. (2020) Phase I clinical trial of selinexor in combination with daunorubicin and cytarabine in previously untreated poor-risk acute myeloid leukemia, Clin. Cancer Res., 26, 54-60, https://doi.org/10.1158/1078-0432.CCR-19-2169.

    Article  CAS  PubMed  Google Scholar 

  119. Martinez Sanchez, M. P., Megias-Vericat, J. E., Rodriguez-Veiga, R., Vives, S., Bergua, J. M., et al. (2021) A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients, Ann. Hematol., 100, 1497-1508, https://doi.org/10.1007/s00277-021-04542-8.

    Article  CAS  PubMed  Google Scholar 

  120. Fiedler, W., Chromik, J., Amberg, S., Kebenko, M., Thol, F., et al. (2020) A Phase II study of selinexor plus cytarabine and idarubicin in patients with relapsed/refractory acute myeloid leukaemia, Br. J. Haematol., 190, e169-e173, https://doi.org/10.1111/bjh.16804.

    Article  CAS  PubMed  Google Scholar 

  121. Taylor, J., Mi, X., Penson, A. V., Paffenholz, S. V., Alvarez, K., Sigler, A., et al. (2020) Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial, Lancet Haematol., 7, e566-e574, https://doi.org/10.1016/S2352-3026(20)30209-X.

    Article  PubMed  Google Scholar 

  122. Chen, C., Siegel, D., Gutierrez, M., Jacoby, M., Hofmeister, C. C., et al. (2018) Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia, Blood, 131, 855-863, https://doi.org/10.1182/blood-2017-08-797886.

    Article  CAS  PubMed  Google Scholar 

  123. Vogl, D. T., Dingli, D., Cornell, R. F., Huff, C. A., Jagannath, S., et al. (2018) Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma, J. Clin. Oncol., 36, 859-866, https://doi.org/10.1200/JCO.2017.75.5207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chari, A., Vogl, D. T., Gavriatopoulou, M., Nooka, A. K., Yee, A. J., et al. (2019) Oral selinexor-dexamethasone for triple-class refractory multiple myeloma, N. Engl. J. Med., 381, 727-738, https://doi.org/10.1056/NEJMoa1903455.

    Article  CAS  PubMed  Google Scholar 

  125. Bahlis, N. J., Sutherland, H., White, D., Sebag, M., Lentzsch, S., et al. (2018) Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma, Blood, 132, 2546-2554, https://doi.org/10.1182/blood-2018-06-858852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jakubowiak, A. J., Jasielec, J. K., Rosenbaum, C. A., Cole, C. E., Chari, A., et al. (2019) Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma, Br. J. Haematol., 186, 549-560, https://doi.org/10.1111/bjh.15969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Salcedo, M., Lendvai, N., Mastey, D., Schlossman, J., Hultcrantz, M., et al. (2020) Phase I study of selinexor, ixazomib, and low-dose dexamethasone in patients with relapsed or refractory multiple myeloma, Clin. Lymphoma Myeloma Leuk., 20, 198-200, https://doi.org/10.1016/j.clml.2019.12.013.

    Article  PubMed  Google Scholar 

  128. Grosicki, S., Simonova, M., Spicka, I., Pour, L., Kriachok, I., et al. (2020) Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): A randomised, open-label, phase 3 trial, Lancet, 396, 1563-1573, https://doi.org/10.1016/S0140-6736(20)32292-3.

    Article  CAS  PubMed  Google Scholar 

  129. Kuruvilla, J., Savona, M., Baz, R., Mau-Sorensen, P. M., Gabrail, N., et al. (2017) Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma, Blood, 129, 3175-3183, https://doi.org/10.1182/blood-2016-11-750174.

    Article  CAS  PubMed  Google Scholar 

  130. Kalakonda, N., Maerevoet, M., Cavallo, F., Follows, G., Goy, A., et al. (2020) Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial, Lancet Haematol., 7, e511-e522, https://doi.org/10.1016/S2352-3026(20)30120-4.

    Article  PubMed  Google Scholar 

  131. Tang, T., Martin, P., Somasundaram, N., Lim, C., Tao, M., et al. (2020) Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or naturalkiller/T-cell lymphoma, Haematologica, 6, 3170-3175, https://doi.org/10.3324/haematol.2020.251454.

    Article  CAS  Google Scholar 

  132. Abdul Razak, A. R., Mau-Soerensen, M., Gabrail, N. Y., Gerecitano, J. F., Shields, A. F., et al. (2016) First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors, J. Clin. Oncol., 34, 4142-4150, https://doi.org/10.1200/JCO.2015.65.3949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wei, X. X., Siegel, A. P., Aggarwal, R., Lin, A. M., Friedlander, T. W., et al. (2018) A phase II trial of selinexor, an oral selective inhibitor of nuclear export compound, in abiraterone- and/or enzalutamide-refractory Metastatic castration-resistant prostate cancer, Oncologist, 23, 656-e664, https://doi.org/10.1634/theoncologist.2017-0624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Shafique, M., Ismail-Khan, R., Extermann, M., Sullivan, D., Goodridge, D., et al. (2019) A phase II trial of selinexor (KPT-330) for metastatic triple-negative breast cancer, Oncologist, 24, 887-e416, https://doi.org/10.1634/theoncologist.2019-0231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Vergote, I. B., Lund, B., Peen, U., Umajuridze, Z., Mau-Sorensen, M., et al. (2020) Phase 2 study of the exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecol. Oncol., 156, 308-314, https://doi.org/10.1016/j.ygyno.2019.11.012.

    Article  CAS  PubMed  Google Scholar 

  136. Rubinstein, M. M., Grisham, R. N., Cadoo, K., Kyi, C., Tew, W. P., et al. (2021) A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers, Gynecol. Oncol., 160, 71-76, https://doi.org/10.1016/j.ygyno.2020.10.019.

    Article  CAS  PubMed  Google Scholar 

  137. Gounder, M. M., Zer, A., Tap, W. D., Salah, S., Dickson, M. A., et al. (2016) 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., 34, 3166-3174, https://doi.org/10.1200/JCO.2016.67.6346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Nilsson, S., Stein, A., Rolfo, C., Kranich, A. L., Mann, J., et al. (2020) Selinexor (KPT-330), an oral Selective Inhibitor of Nuclear Export (SINE) compound, in combination with FOLFOX in patients with metastatic colorectal cancer (mCRC) – final results of the phase I trial SENTINEL, Curr. Cancer Drug Targets, 20, 811-817, https://doi.org/10.2174/1568009620666200628105727.

    Article  CAS  PubMed  Google Scholar 

  139. (2019) XPO1 inhibitor approved for multiple myeloma, Cancer Discov., 9, 1150-1151, https://doi.org/10.1158/2159-8290.CD-NB2019-085.

  140. Cornell, R., Hari, P., Tang, S., Biran, N., Callander, N., et al. (2021) Overall survival of patients with triple-class refractory multiple myeloma treated with selinexor plus dexamethasone vs standard of care in MAMMOTH, Am. J. Hematol., 96, E5-E8, https://doi.org/10.1002/ajh.26010.

    Article  CAS  PubMed  Google Scholar 

  141. Machlus, K. R., Wu, S. K., Vijey, P., Soussou, T. S., Liu, Z. J., et al. (2017) Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis, Blood, 130, 1132-1143, https://doi.org/10.1182/blood-2016-11-752840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors dedicate this work to their dear teacher Lev Ovchinnikov, an exceptional mentor who helped shape their scientific careers.

Author information

Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA

    Ekaterina Kim & Alexey Sorokin

  2. Institute of Protein Research, Russian Academy of Sciences, 142290, Pushchino, Moscow Region, Russia

    Daria A. Mordovkina

Authors
  1. Ekaterina Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daria A. Mordovkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexey Sorokin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ekaterina Kim.

Ethics declarations

The authors declare no conflicts of interest. This article does not contain description of studies with the involvement of humans or animal subjects performed by any of the authors.

Additional information

Translated from Uspekhi Biologicheskoi Khimii, 2022, Vol. 62, pp. 391-420.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, E., Mordovkina, D.A. & Sorokin, A. Targeting XPO1-Dependent Nuclear Export in Cancer. Biochemistry Moscow 87 (Suppl 1), S178–S191 (2022). https://doi.org/10.1134/S0006297922140140

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297922140140

Keywords

Search

Navigation