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

Leukemia. 2013 Dec;27(12):2357-65. doi: 10.1038/leu.2013.172. Epub 2013 Jun 11.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01607892.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Acrylamides / pharmacology*
  • Animals
  • Biological Transport / drug effects*
  • Cell Line, Tumor
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Gene Expression Profiling
  • Genome-Wide Association Study*
  • Humans
  • Karyopherins / drug effects
  • Karyopherins / genetics*
  • Mice
  • Multiple Myeloma / genetics*
  • RNA Interference
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thiazoles / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Acrylamides
  • KPT-276
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • exportin 1 protein

Associated data

  • ClinicalTrials.gov/NCT01607892