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

Abstract

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers. Mol Cancer Ther; 15(1); 60-71. Ó2015 AACR.

Therapy for Relapsed Multiple Myeloma

“…These include the oral PI oprozomib 103 that is related to carfilzomib and marizomib 104 ; dinaciclib, 105 an oral cyclin-dependent kinase inhibitor; selinexor, 106 a selective inhibitor of exportin 1; venetoclax, 107 a selective inhibitor of bcl-2, and isatuximab, 108 a novel MAb that also targets CD38 and may have a more favorable pharmacological profile than does daratumumab. Other agents in early clinical trials include immune checkpoint inhibitors (pembrolizumab and nivolumab) and chimeric antigen receptor T cells.…”

Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

“…Preclinical studies have provided a rationale for combining selinexor with PIs (Kashyap et al , ; Nair et al , ; Rosebeck et al , ; Turner et al , ). The addition of selinexor to a PI has a synergistic effect on cell death of myeloma cell lines and primary plasma cells derived from patients with RRMM, and the combination demonstrated greater antimyeloma activity in a murine xenograft model than either agent alone (Kashyap et al , ; Rosebeck et al , ; Turner et al , ).…”

“…Preclinical studies have provided a rationale for combining selinexor with PIs (Kashyap et al , ; Nair et al , ; Rosebeck et al , ; Turner et al , ). The addition of selinexor to a PI has a synergistic effect on cell death of myeloma cell lines and primary plasma cells derived from patients with RRMM, and the combination demonstrated greater antimyeloma activity in a murine xenograft model than either agent alone (Kashyap et al , ; Rosebeck et al , ; Turner et al , ). Selinexor‐PI combinations were associated with inhibition of BCL2 expression, increased cleavage and inactivation of AKT, activation of caspase‐10 and other caspases, and increased levels of IκBα and IκBα‐NFκB complexes, leading to neutralization of NF‐κB (Kashyap et al , ; Rosebeck et al , ; Turner et al , ).…”

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

“…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] . The combination of selinexor and doxorubicin was highly effective against acquired drug resistance in ex vivo samples obtained from patients with either relapsed or refractory myeloma as well as in vivo xenograft models of myeloma.…”