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Nucleo-cytoplasmic transport as a therapeutic target of cancer

Giovanni Luca Gravina, William Senapedis, Dilara McCauley

    Journal of Hematology & Oncology
    |December 6, 2014
    PubMed

    Insights

    Nuclear export via XPO1 regulates cell cycle and proliferation. Inhibiting XPO1, the main mediator of nuclear export, offers a promising therapeutic strategy for various cancers, with selective inhibitors like selinexor showing clinical potential.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cell Biology

    Background:

    • Nuclear export is crucial for cell cycle regulation and proliferation in normal and malignant tissues.
    • XPO1 (Exportin-1/CRM1) is the primary mediator of nuclear export, controlling the localization of key proteins like tumor suppressors and oncogenes.
    • Dysregulation of XPO1-mediated nuclear export is implicated in tumor growth, inflammation, and apoptosis, with elevated XPO1 levels observed in several cancers.

    Purpose of the Study:

    • To highlight the critical role of XPO1 in cancer progression and its potential as a therapeutic target.
    • To review the mechanisms by which XPO1 influences cell proliferation and cancer development.
    • To discuss the development and therapeutic potential of XPO1 inhibitors, particularly selective inhibitors of nuclear export (SINE compounds).

    Main Methods:

    • Review of existing literature on XPO1 function, its role in various cancers, and the development of nuclear export inhibitors (NEIs).
    • Analysis of the mechanisms of XPO1-mediated nuclear export, including its impact on cell cycle and tumor suppressor proteins.
    • Examination of the preclinical and clinical data for XPO1 inhibitors, focusing on SINE compounds like selinexor and verdinexor.

    Main Results:

    • XPO1 mediates the export of critical proteins, including tumor suppressors (Rb, p53) and oncogenes (BCR-ABL), influencing cell proliferation and tumor growth.
    • Elevated XPO1 expression is a hallmark of several solid tumors, suggesting its role as a prognostic marker.
    • Selective inhibitors of nuclear export (SINEs), such as selinexor (KPT-330), are orally bioavailable, potent, and are progressing through clinical trials for hematological and solid cancers.

    Conclusions:

    • XPO1 is a central regulator of nuclear export and plays a significant role in cancer pathogenesis.
    • Inhibition of XPO1 represents a promising therapeutic strategy for a range of cancers.
    • XPO1 is an advanced and well-understood therapeutic target for cancer treatment, with SINEs demonstrating significant clinical potential.

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