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  • Review Article
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The nuclear export protein XPO1 — from biology to targeted therapy

Nature Reviews Clinical Oncology volume 18, pages 152–169 (2021)Cite this article

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An Author Correction to this article was published on 24 November 2020

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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.

Key points

  • The nuclear export protein exportin 1 (XPO1) is crucial for the maintenance of cellular homeostasis as it mediates the transport of >200 proteins, many of which are tumour suppressors, from the nucleus to the cytoplasm, making XPO1 a promising target for cancer therapy.

  • Early XPO1 inhibitors achieved limited success owing to toxicities, although more selective inhibitors of XPO1 have been developed, with promising results. This advance has led to the FDA approval of selinexor as a fifth-line therapy for multiple myeloma and as a third-line therapy for diffuse large B cell lymphoma.

  • Early signs of therapeutic activity of selinexor have been demonstrated in patients with lymphoma, glioblastoma and other solid tumours in which conventional therapies have been unsuccessful.

  • No predictive biomarkers of a response to selinexor have been recognized thus far, which obstructs the further development of this agent and its related compounds.

  • Clinical and preclinical investigations are assessing combinations of selinexor with standard-of-care therapies, including other targeted agents, in an attempt to overcome acquired resistance and to improve the therapeutic outcomes.

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Fig. 1: Schematic representation of XPO1-mediated nuclear export.
Fig. 2: Gradient of RanGTP across the nuclear membrane.
Fig. 3: XPO1 mediated nuclear export and mechanisms of oncogenesis.
Fig. 4: The role of XPO1 in acquired drug resistance.

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Acknowledgements

Given the space limitations of this Review, the authors apologize for their inability to cite all relevant studies. Work in the lab of A.S.A. is supported by NIH R37CA215427.

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  1. Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Asfar S. Azmi, Mohammed H. Uddin & Ramzi M. Mohammad

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A.S.A., M.H.U. and R.M.M. made substantial contributions to each stage of the preparation of this manuscript for publication.

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Correspondence to Ramzi M. Mohammad.

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A.S.A. has acted as a consultant of GLG Consulting and GuidePoint, has received research grants from EISAI Janssen and Rhizen and has been a speaker at an event organized by Karyopharm. The author’s institution has received research funding (partially supporting the phase Ib/II studies NCT02178436 and NCT03147885) from Karyopharm. M.H.U. and R.M.M. declare no competing interests.

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Azmi, A.S., Uddin, M.H. & Mohammad, R.M. The nuclear export protein XPO1 — from biology to targeted therapy. Nat Rev Clin Oncol 18, 152–169 (2021). https://doi.org/10.1038/s41571-020-00442-4

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