Selinexor for myelofibrosis or a drug in search of a disease?

Selinexor is an oral selective inhibitor of nuclear export (SINE) that targets exportin-1 (XPO1), a key regulator of nuclear-cytoplasmic transport [ 1 ]. Inhibition of XPO1 results in nuclear entrapment of tumor suppressor proteins and growth regulators, resulting in their reactivation and induction of apoptosis in malignant cells [ 1 ]. Such a mechanism of action suggests the potential for non-specific therapeutic activity that extends across a broad range of hematologic malignancies. The drug is currently approved for the treatment of multiple myeloma and was previously approved for relapsed/refractory diffuse large B-cell lymphoma, although this indication has since been withdrawn [ 2 , 3 ]. Preclinical studies have also suggested a therapeutic role in myelofibrosis (MF) by identifying XPO1 as a therapeutic vulnerability in JAK2V617F -mutant cells by selectively suppressing clonal cells while sparing normal progenitors and demonstrating activity in murine models [ 4 , 5 ].