Journal Article

Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276

Braggio, E, Bergsagel, P L, Stewart, A K, Palmer, S E, Zhu, Y X, Xin, C S, Tiedemann, R E, Kauffman, M, McCauley, D, Kortuem, K M, Egan, J B, Chesi, M, Schmidt, J, Shacham, S, Garbitt, V M

2013

Overview

RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells ( P <0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM ( P <0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1 . The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A ( CDC25A ) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/555 / 631/208/205/2138 / 631/80/389 / 692/699/67/1990/804 / Acrylamides - pharmacology / Animals / Antimitotic agents / Antineoplastic agents / Apoptosis / Biological Transport - drug effects / c-Myc protein / Cancer Research / Cancer therapies / Care and treatment / Carrier proteins / Cell cycle / Cell division / Cell Line, Tumor / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Clinical trials / Critical Care Medicine / Disease progression / Dosage and administration / Exportin 1 Protein / Gene expression / Gene Expression Profiling / Genes / Genetic aspects / Genome-Wide Association Study / Genomes / Hematology / Homology / Humans / Identification and classification / Inhibitors / Intensive / Internal Medicine / Karyopherins - drug effects / Karyopherins - genetics / Leukemia / Medical prognosis / Medicine / Medicine & Public Health / Mice / Monoclonal gammopathy / Multiple myeloma / Multiple Myeloma - genetics / Myc protein / Nuclear transport / Oncology / original-article / Patients / Penicillin / Plasma cells / Protein transport / Proteins / Receptors, Cytoplasmic and Nuclear - drug effects / Receptors, Cytoplasmic and Nuclear - genetics / Reverse Transcriptase Polymerase Chain Reaction / Reverse transcription / RNA Interference / RNA transport / RNA-mediated interference / Smoldering / Thiazoles - pharmacology / Tumors / Western blotting / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation