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

This study explored the anti‐leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T‐cell acute lymphoblastic leukaemia (T‐ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti‐leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T‐ALL MOLT‐4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti‐leukaemic efficacy of the clinical SINE compound KPT‐330 against T‐ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT‐330 against T‐ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising ‘first‐in‐class’ drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T‐ALL and AML.

[1]  Victoria Del Gaizo Moore,et al.  BH3 profiling--measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions. , 2013, Cancer letters.

[2]  Yuh Min Chook,et al.  Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. , 2012, Blood.

[3]  N. Grishin,et al.  NESdb: a database of NES-containing CRM1 cargoes , 2012, Molecular biology of the cell.

[4]  Nick V. Grishin,et al.  Sequence and structural analyses of nuclear export signals in the NESdb database , 2012, Molecular biology of the cell.

[5]  Guido Marcucci,et al.  Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. , 2012, Blood.

[6]  A T Look,et al.  Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells , 2012, Leukemia.

[7]  D. Sullivan,et al.  Nuclear export of proteins and drug resistance in cancer. , 2012, Biochemical pharmacology.

[8]  Donald W Kufe,et al.  CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity. , 2011, Blood.

[9]  Yuh Min Chook,et al.  Recognition of nuclear targeting signals by Karyopherin-β proteins. , 2010, Current opinion in structural biology.

[10]  Michael Sattler,et al.  NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1 , 2010, Nature Structural &Molecular Biology.

[11]  Mingming Jia,et al.  COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer , 2010, Nucleic Acids Res..

[12]  A. Letai,et al.  Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes , 2010, Proceedings of the National Academy of Sciences.

[13]  Karl Gademann,et al.  The cytotoxic styryl lactone goniothalamin is an inhibitor of nucleocytoplasmic transport. , 2010, Bioorganic & medicinal chemistry letters.

[14]  Karl Gademann,et al.  Anguinomycins and derivatives: total syntheses, modeling, and biological evaluation of the inhibition of nucleocytoplasmic transport. , 2010, Journal of the American Chemical Society.

[15]  Li-wei Wang,et al.  Prognostic value of CRM1 in pancreas cancer. , 2009, Clinical and investigative medicine. Medecine clinique et experimentale.

[16]  Li-wei Wang,et al.  Prognostic value of CRM1in pancreas cancer , 2009 .

[17]  Peter Washausen,et al.  Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition. , 2009, Cancer research.

[18]  Chun Cheng,et al.  EXPRESSION OF CRM1 IN HUMAN GLIOMAS AND ITS SIGNIFICANCE IN P27 EXPRESSION AND CLINICAL PROGNOSIS , 2009, Neurosurgery.

[19]  Thomas Monecke,et al.  Crystal Structure of the Nuclear Export Receptor CRM1 in Complex with Snurportin1 and RanGTP , 2009, Science.

[20]  M. Birrer,et al.  The Karyopherin proteins, Crm1 and Karyopherin β1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation , 2009, International journal of cancer.

[21]  S. Mutka,et al.  Identification of nuclear export inhibitors with potent anticancer activity in vivo. , 2009, Cancer research.

[22]  Wim Dehaen,et al.  Inhibition of the CRM1-mediated nucleocytoplasmic transport by N-azolylacrylates: structure-activity relationship and mechanism of action. , 2008, Bioorganic & medicinal chemistry.

[23]  Carsten Denkert,et al.  Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer , 2008, Cancer.

[24]  S A Forbes,et al.  The Catalogue of Somatic Mutations in Cancer (COSMIC) , 2008, Current protocols in human genetics.

[25]  Charles Lee,et al.  Alu elements mediate MYB gene tandem duplication in human T-ALL , 2007, The Journal of experimental medicine.

[26]  Govind Bhagat,et al.  Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia , 2007, Nature Medicine.

[27]  L. Chin,et al.  Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers , 2007, Nature.

[28]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[29]  Gerard I. Evan,et al.  Modeling the Therapeutic Efficacy of p53 Restoration in Tumors , 2006, Cell.

[30]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[31]  U. Vinkemeier,et al.  Ratjadone and leptomycin B block CRM1‐dependent nuclear export by identical mechanisms , 2004, FEBS letters.

[32]  A. Ferrando,et al.  Gene expression profiling in T-cell acute lymphoblastic leukemia. , 2003, Seminars in hematology.

[33]  J. Kjems,et al.  A synthetic HIV-1 Rev inhibitor interfering with the CRM1-mediated nuclear export , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  N. Kudo,et al.  Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Minoru Yoshida,et al.  CRM1 is responsible for intracellular transport mediated by the nuclear export signal , 1997, Nature.

[36]  C. Dargemont,et al.  Evidence for a role of CRM1 in signal-mediated nuclear protein export. , 1997, Science.

[37]  Minoru Yoshida,et al.  CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals , 1997, Cell.

[38]  K. Borden,et al.  mRNA export and cancer , 2012, Wiley interdisciplinary reviews. RNA.

[39]  Yuh Min Chook,et al.  Structural basis for leucine-rich nuclear export signal recognition by CRM1 , 2009, Nature.

[40]  Y. Dong,et al.  The expression of CRM1 is associated with prognosis in human osteosarcoma. , 2009, Oncology reports.

[41]  S. Armstrong,et al.  Molecular genetics of acute lymphoblastic leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  G. Paolucci,et al.  [Treatment of acute lymphoblastic leukemia]. , 1971, Minerva pediatrica.