Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Experimental Hematology & Oncology
Published in: Experimental Hematology & Oncology 1/2015

Open Access 01-12-2015 | Review

Selective inhibitors of nuclear export (SINE) in hematological malignancies

Authors: Arundhati Das, Guoqing Wei, Kaushal Parikh, Delong Liu

Published in: Experimental Hematology & Oncology | Issue 1/2015

Login to get access

Abstract

Regulated nucleo-cytoplasmic transport plays a major role in maintaining cellular homeostasis. CRM1 (chromosome region maintenance 1 or exportin 1 or XPO 1) is responsible for the nucleo-cytoplasmic transport of more than 200 proteins, including most of the tumor suppressor proteins (TSP). CRM1 is overexpressed in pancreatic cancer, osteosarcoma, glioma, cervical and hematological malignancies. This inspired the development of novel agents that selectively inhibit nuclear exportins (SINEs). In this review we focus on the significance of CRM1 in carcinogenesis and review the new development of SINE inhibitiors in hematological malignancies. Selinexor (KPT-330) as the first-in-human SINE agent represents this novel class of anti-cancer agents.
Literature
1.
Dong X, Biswas A, Suel KE, Jackson LK, Martinez R, Gu H, et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature. 2009;458(7242):1136–41.CrossRefPubMedCentralPubMed
2.
Fung HY, Chook YM. Atomic basis of CRM1-cargo recognition, release and inhibition. Semin Cancer Biol. 2014;27:52–61.CrossRefPubMed
3.
4.
5.
6.
Adachi Y, Yanagida M. Higher order chromosome structure is affected by cold-sensitive mutations in a Schizosaccharomyces pombe gene crm1+ which encodes a 115-kD protein preferentially localized in the nucleus and its periphery. J Cell Biol. 1989;108(4):1195–207.CrossRefPubMed
7.
Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90(6):1051–60.CrossRefPubMed
8.
9.
Petosa C, Schoehn G, Askjaer P, Bauer U, Moulin M, Steuerwald U, et al. Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex. Mol Cell. 2004;16(5):761–75.CrossRefPubMed
10.
Nobumori Y, Shouse GP, Fan L, Liu X. HEAT repeat 1 motif is required for B56gamma-containing protein phosphatase 2A (B56gamma-PP2A) holoenzyme assembly and tumor-suppressive function. J Biol Chem. 2012;287(14):11030–6.CrossRefPubMedCentralPubMed
11.
Turner JG, Sullivan DM. CRM1-mediated nuclear export of proteins and drug resistance in cancer. Curr Med Chem. 2008;15(26):2648–55.CrossRefPubMed
12.
Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y, et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood. 2012;120(23):4621–34.CrossRefPubMedCentralPubMed
13.
14.
Gravina G, Tortoreto M, Mancini A, Addis A, Di Cesare E, Lenzi A, et al. XPO1/CRM1-selective inhibitors of nuclear export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa). J Hematol Oncol. 2014;7(1):46.CrossRefPubMedCentralPubMed
15.
Gerecitano J. SINE (selective inhibitor of nuclear export) - translational science in a new class of anti-cancer agents. J Hematol Oncol. 2014;7(1):67.CrossRefPubMedCentralPubMed
16.
17.
Foran JM. New prognostic markers in acute myeloid leukemia: perspective from the clinic. Hematology Am Soc Hematol Educ Program. 2010;2010:47–55.CrossRefPubMed
18.
19.
Loghavi S, Zuo Z, Ravandi F, Kantarjian H, Bueso-Ramos C, Zhang L, et al. Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. J Hematol Oncol. 2014;7(1):74.CrossRefPubMedCentralPubMed
20.
Pastore F, Kling D, Hoster E, Dufour A, Konstandin N, Schneider S, et al. Long-term follow-up of cytogenetically normal CEBPA-mutated AML. J Hematol Oncol. 2014;7(1):55.CrossRefPubMedCentralPubMed
21.
Luo J, Qi C, Xu W, Kamel-Reid S, Brandwein J, Chang H. Cytoplasmic expression of nucleophosmin accurately predicts mutation in the nucleophosmin gene in patients with acute myeloid leukemia and normal karyotype. Am J Clin Pathol. 2010;133(1):34–40.CrossRefPubMed
22.
Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M, et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood. 2012;120(9):1765–73.CrossRefPubMedCentralPubMed
23.
Kojima K, Kornblau SM, Ruvolo V, Dilip A, Duvvuri S, Davis RE, et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood. 2013;121(20):4166–74.CrossRefPubMedCentralPubMed
24.
Etchin J, Sanda T, Mansour MR, Kentsis A, Montero J, Le BT, et al. 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. 2013;161(1):117–27.CrossRefPubMedCentralPubMed
25.
Walker CJ, Oaks JJ, Santhanam R, Neviani P, Harb JG, Ferenchak G, et al. Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood. 2013;122(17):3034–44.CrossRefPubMedCentralPubMed
26.
Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014;28(1):155–65.CrossRefPubMedCentralPubMed
27.
Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27(12):2357–65.CrossRefPubMedCentralPubMed
28.
Azmi AS, Al-Katib A, Aboukameel A, McCauley D, Kauffman M, Shacham S, et al. Selective inhibitors of nuclear export for the treatment of non-Hodgkin’s lymphomas. Haematologica. 2013;98(7):1098–106.CrossRefPubMedCentralPubMed
29.
Yoshimura M, Ishizawa J, Ruvolo V, Dilip A, Quintas-Cardama A, McDonnell TJ, et al. Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. Cancer Sci. 2014;105(7):795–801.CrossRefPubMed
30.
Zhang K, Wang M, Tamayo AT, Shacham S, Kauffman M, Lee J, et al. Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma. Exp Hematol. 2013;41(1):67–78. e64.CrossRefPubMed
31.
London CA, Bernabe LF, Barnard S, Kisseberth WC, Borgatti A, Henson M, et al. Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study. PLoS One. 2014;9(2):e87585.CrossRefPubMedCentralPubMed
32.
Gutierrez M, Goy A, Byrd JC, Flynn JM, Sorensen M, Brown P, et al. A phase 1 dose-escalation study of the oral selective inhibitor of nuclear export (SINE) KPT-330 (selinexor) in patients (pts) with heavily pretreated non-Hodgkin lymphoma (NHL). ASCO Meeting Abstracts. 2014;32(15):8518.
33.
Gravina G, Senapedis W, McCauley D, Baloglu E, Shacham S, Festuccia C. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7(1):85.CrossRefPubMedCentralPubMed
Metadata
Title
Selective inhibitors of nuclear export (SINE) in hematological malignancies
Authors
Arundhati Das
Guoqing Wei
Kaushal Parikh
Delong Liu
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2015
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/s40164-015-0002-5

Other articles of this Issue 1/2015

Experimental Hematology & Oncology 1/2015 Go to the issue

Research

Analysis of the anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple myeloma

Research

Tissue factor-dependent and -independent pathways of systemic coagulation activation in acute myeloid leukemia: a single-center cohort study

Case report

Refractory myeloid sarcoma with a FIP1L1-PDGFRA rearrangement detected by clinical high throughput somatic sequencing

Review

Allogeneic hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: potential benefit of medium-dose etoposide conditioning

Research

Lactate, a putative survival factor for myeloma cells, is incorporated by myeloma cells through monocarboxylate transporters 1

Short report

CD57+ T-cells are a subpopulation of T-follicular helper cells in nodular lymphocyte predominant Hodgkin lymphoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits