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Exportin 1 (XPO1) nuclear export inhibitor
Selinexor is an inhibitor of XPO1 and represents the first-in-class nuclear export inhibitor (or SINE).172 Regulated nucleo-cytoplasmic transport plays a major role in maintaining cellular homeostasis, and cancer cells routinely utilize these processes to evade normal apoptotic mechanisms.173,174 XPO1 (also known as chromosome maintenance protein 1) binds mRNA and cellular cargo proteins containing a leucine-rich NES and directs their active transport from the cell nucleus to the cytoplasm through the nuclear pore complex.172,173,175–177 XPO1 serves as the primary mediator for the export of over 220 proteins and is the exclusive exporter of p21, p53, p73, CDKN1A, RB, BRCA1, FOXO, APC, NPM1, and STAT39.172,175,177 XPO1 overexpression is common to many human cancers and is responsible for enhanced inactivation of tumor suppressor proteins, apoptosis inducers, and cell cycle regulators.46,172,174,177,178 Selinexor selectively binds to Cys528 of XPO1 to prevent XPO1 binding to the NES domains on cargo proteins.175,177,179,180 By hindering the protein expression of cancer-related genes, XPO1 silencing by selinexor induces cell cycle arrest and apoptosis. Selinexor and other SINEs are being studied for a variety of cancers in more than 60 registered clinical trials.173,180–183
On the basis of overall response rate (21/83 patients) in a multicenter, single-arm, open-label study (STORM Part 2; NCT02336815),179,184 selinexor was granted accelerated approval in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and one anti‐CD38 monoclonal antibody (i.e., for patients who have exhausted all other treatment options).46,47 The median response duration was 3.8 months.46,47
Significant toxicities (nausea, vomiting, diarrhea, anorexia, weight loss, fatigue, dizziness, confusion, anemia, hyponatremia, neutropenia, and thrombocytopenia) limit the tolerability of selinexor.46 One hundred percent of patients can be expected to develop one or more treatment-emergent adverse effects.179,184 The recommended starting dose is 80 mg, adjusted for the development of toxicities according to the schedule published in the product labeling.46 Selinexor is taken orally, in combination with 20 mg of dexamethasone (for therapeutic synergy)180,185 and an antiemetic (to improve tolerability), on days 1 and 3 of each week, until disease progression or unacceptable toxicity occurs. The median duration of exposure to the target dose of 80 mg in the STORM study was 3.5 weeks (i.e., seven doses).172,179 The mean half‐life of selinexor is 6–8 hours.46 It is metabolized by CYP3A4, UGTs, and GSTs.46 Selinexor is an inhibitor of OATP1B3.46 Selinexor is embryo‐fetal toxic, requiring effective contraception during therapy and for 1 week following discontinuation of therapy.46 The cost of therapy is estimated to be $22,000 per month.186 The chemical structure of selinexor is shown in Figure P1–3.
Chapter 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein Kinase Inhibitors, and Various Small Molecules
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals