Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Abstract

Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published.

Keywords

XPO1 / CRM1 / nucleocytoplasmic transport / Selinexor

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