The nuclear export protein XPO1 — from biology to targeted therapy
Top Cited Papers
- 10 November 2020
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Clinical Oncology
- Vol. 18 (3), 152-169
- https://doi.org/10.1038/s41571-020-00442-4
Abstract
Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma. In this Review, we summarize the progress and challenges in the development of nuclear export inhibitors and discuss the potential of emerging combination therapies and biomarkers of response.Keywords
This publication has 193 references indexed in Scilit:
- ValidNESs: a database of validated leucine-rich nuclear export signalsNucleic Acids Research, 2012
- Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cellsLeukemia, 2012
- Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemiaProceedings of the National Academy of Sciences of the United States of America, 2011
- Silencing Nuclear Pore Protein Tpr Elicits a Senescent-Like Phenotype in Cancer CellsPLOS ONE, 2011
- Comparative Genomic Evidence for a Complete Nuclear Pore Complex in the Last Eukaryotic Common AncestorPLOS ONE, 2010
- Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabineProceedings of the National Academy of Sciences of the United States of America, 2010
- Dynamics of galectin-3 in the nucleus and cytoplasmBiochimica et Biophysica Acta (BBA) - General Subjects, 2010
- Aberrant Cytoplasmic Expression of p63 and Prostate Cancer MortalityCancer Epidemiology, Biomarkers & Prevention, 2009
- Darwinian evolution in the light of genomicsNucleic Acids Research, 2008
- Epidermal Growth Factor Receptor Mutations in Non–Small-Cell Lung Cancer: Implications for Treatment and Tumor BiologyJournal of Clinical Oncology, 2005