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Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear
J Schmidt1, E Braggio, K M Kortuem
1Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA.
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.
Insights
Exportin 1 (XPO1) is a key target in multiple myeloma (MM). A novel inhibitor, KPT-276, effectively reduced MM cell viability and tumor growth in preclinical models, warranting further clinical investigation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- XPO1 (exportin 1) is identified as a critical target in multiple myeloma (MM).
- XPO1 expression is elevated in MM patients and correlates with disease progression.
- XPO1 is overexpressed in human MM cell lines (HMCLs).
Purpose of the Study:
- To investigate the therapeutic potential of targeting XPO1 in multiple myeloma.
- To evaluate the efficacy of the selective nuclear export inhibitor KPT-276 in MM models.
Main Methods:
- RNA interference screening to identify MM targets.
- In vitro treatment of HMCLs and primary MM patient samples with KPT-276.
- Gene expression analysis (Western blotting, RT-PCR) for c-MYC, CDC25A, and BRD4.
- In vivo studies using Vk*MYC transgenic and xenograft MM mouse models.
Main Results:
- KPT-276 significantly reduced the viability of HMCLs and induced apoptosis in primary MM samples.
- KPT-276 downregulated c-MYC, CDC25A, and BRD4, genes associated with the c-MYC pathway.
- KPT-276 inhibited tumor growth and reduced monoclonal spikes in preclinical MM mouse models.
Conclusions:
- XPO1 is a validated therapeutic target in multiple myeloma.
- Selective inhibition of XPO1 with KPT-276 demonstrates significant anti-myeloma activity in vitro and in vivo.
- The findings support ongoing clinical trials of XPO1 inhibitors in hematological malignancies.
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