Combination Therapies Including XPO1 Inhibitor May Be Effective Against Myelofibrosis

The use of combination therapies including the exportin 1 (XPO1) inhibitor selinexor is a potentially effective therapeutic strategy to treat patients with myelofibrosis (MF), according to a study presented at the 65th American Society of Hematology Annual Meeting and Exposition by Min Lu, PhD, MD, of the Icahn School of Medicine at Mount Sinai in Elmhurst, New York, and colleagues.

XPO1 is frequently overexpressed or mutated in human cancers and functions as an oncogenic driver. Suppression of XPO1-mediated nuclear export is known to be a potential therapeutic strategy to treat patients with MF. The investigational, oral XPO1 inhibitor selinexor may inhibit multiple pathways relevant in MF, including JAK/STAT, ERK, and AKT, according to the researchers.

The study tested the effects of selinexor on apoptosis and cell cycle arrest in JAK2^V617F cells with either wild-type or mutated TP53 and evaluated the ability of selinexor to eliminate MF CD34⁺ cells alone and in combination with other candidate drugs, such as HDM201 (an HDM2 antagonist) and ruxolitinib.

The results showed that treatment with selinexor alone induced apoptosis of both wild-type TP53 (UKE-1) and mutated TP53 (SET-2) MPN CD34⁺ cell lines in a dose-dependent fashion. Selinexor and HDM201 alone induced apoptosis of primary MF but not healthy donor CD34+ cells in a dose-dependent fashion.

In combination, selinexor combined with either ruxolitinib or HDM201 more effectively depleted mutated MF CD34+ cells than either drug alone. In particular, the combination of selinexor plus HDM201 spared the reservoir of wild-type progenitors and reduced JAK2-mutated progenitor cells to a great degree, suggesting that this combination might be associated with less hematological toxicity and greater efficacy.

Reference

Lu M, Xia L, Hoffman R. Use of combination therapies including the XPO1 inhibitor selinexor in is a potential effective therapeutic strategy to treat myelofibrosis patients. Abstract #1792. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.