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

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.

Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10–Dependent Apoptosis by Carfilzomib and Selinexor

“…Small molecule, selective inhibitors of nuclear export (SINE) force nuclear retention of deregulated targets by preventing XPO1/ cargo interaction, thereby reestablishing normal tumor suppressive functions and rendering cancer cells responsive to other chemotherapeutics. We and others have demonstrated the cytotoxic effects of SINE in multiple myeloma (4)(5)(6)(7). Currently, multiple phase I/II clinical trials are enrolling to test the efficacy of the orally available SINE, selinexor, in patients with advanced stage pancreatic, prostate, salivary gland, and rectal cancers, glioblastoma, melanoma, non-Hodgkin's lymphoma, acute myeloid leukemia, and relapsed/refractory multiple myeloma (R/R multiple myeloma).…”

“…One manner in which these proteins may be dysregulated is via mislocalization within the cell. Exportin 1 (XPO1; or chromosome maintenance region 1, CRM1) is the prominent nuclear export receptor that controls nucleo-cytoplasmic localization of many proteins (2) and is overexpressed in many cancer types both solid and hematologic in origin, including multiple myeloma as shown by us and others (4)(5)(6), promoting aberrant cytoplasmic accumulation of its cargo. Small molecule, selective inhibitors of nuclear export (SINE) force nuclear retention of deregulated targets by preventing XPO1/ cargo interaction, thereby reestablishing normal tumor suppressive functions and rendering cancer cells responsive to other chemotherapeutics.…”

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

“…CRM1 is upregulated in several types of cancer, and its overexpression correlates with a poor prognosis (11,(13)(14)(15)(16)(17). Importantly, CRM1 inhibition by the potent small-molecule selective inhibitor of nuclear export (SINE), KPT-330, has been suggested as a promising therapeutic option for a number of cancer types (18)(19)(20)(21)(22)(23). In this study, we characterized the biologic significance of CRM1 in the context of EWS and determined the therapeutic merit of CRM1 inhibition for this malignancy.…”

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…The combination of KPT-185 with bortezomib showed synergistic effect on growth arrest in MM cells. However, no synergy was observed with KPT-276 when combined with other chemotherapeutic agents such as bortezomib, dexamethasone and melphalan in a different studies [49] . Interesting, this study found that SINEs suppressed the expression of cell division cycle 25 homolog A, bromodomain-containing protein 4 (BRD4) and c-Myc [49] .…”

“…However, no synergy was observed with KPT-276 when combined with other chemotherapeutic agents such as bortezomib, dexamethasone and melphalan in a different studies [49] . Interesting, this study found that SINEs suppressed the expression of cell division cycle 25 homolog A, bromodomain-containing protein 4 (BRD4) and c-Myc [49] . Moreover, combined treatment with selinexor and carfilzomib caused significant apoptosis of myeloma cells and primary plasma cells derived from relapsing/refractory myeloma patients [50] .…”