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. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

Small Molecule Inhibitors of CRM1

“…RNAi-mediated silencing of the CRM1 induced nuclear retention of p53 and cell death in cervical cancer cell lines (Santiago et al, 2013). Somatic mutations in CRM1 have been identified in chronic lymphocytic leukemia (Puente et al, 2011) and in other hematological malignancies (Sendino et al, 2018). The great majority of these mutations affect a single amino acid at position 571.…”

Targeting Nuclear Export Proteins in Multiple Myeloma Therapy

“…Of these SINEs, KPT-330, otherwise known as selinexor, has demonstrated the most success due to its superior bioavailability and potency [ 32 ]. In preclinical studies, selinexor reduced proliferation and induced growth inhibition and/or apoptosis in MM, AML, chronic lymphocytic lymphoma (CLL), lymphoma, renal, prostate, breast, ovarian, colorectal liver, pancreatic, non-small cell lung cancer, thyroid, sarcoma, mesothelioma, glioma, and melanoma malignancies [ 33 ]. Recently, based on data that XPO inhibition also blocks viral replication and ensuing inflammation, a randomized phase II clinical trial of low-dose selinexor versus placebo in patients hospitalized with severe coronavirus disease 2019 (COVID-19) was also initiated (NCT04349098).…”

Using a Simple Cellular Assay to Map NES Motifs in Cancer-Related Proteins, Gain Insight into CRM1-Mediated NES Export, and Search for NES-Harboring Micropeptides

“…Importantly, this modified reporter, called SRVB/A, was designed in such a manner that candidate NES motifs can be easily shuttled to and from the Rev(1.4)-GFP reporter (Figure 2A). [13]) showing the overlap between the list of potential CRM1 cargos reported in [6] and the group of "Cancer-related gene" defined in the Human Protein Atlas. The 136 common proteins represent what we refer to as the "XPO1/CRM1-cancer exportome".…”

“…To better understand the biological effects of CRM1 inhibitors in cancer patients, it is thus essential to extend our current knowledge of cancer-related CRM1 cargos. In this regard, by combining the "CRM1-dependent nuclear exportome" protein set [6] with the subset of "Cancer-related gene" entries of the Human Protein Atlas (https://www.proteinatlas.org/), we recently proposed the term "XPO1/CRM1-cancer exportome" [13] to refer to a group of 136 cancer-related proteins that are known or potential CRM1 cargos ( Supplementary Table S1. Importantly, the NES motifs that could mediate CRM1-dependent export of these proteins remain unknown in most cases.…”