Atovaquone and selinexor as a novel combination treatment option in acute myeloid leukemia

Research output: Journal article (peer-reviewed)Journal article

Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia and is predominantly affecting the elderly. It is a heterogenous disease, showing a broad spectrum of genomic alterations and mutations that influence the clinical outcome and treatment options. The expression of the signal transducer and activator of transcription 3 (STAT3) is often dysregulated in AML and its constitutive activation is associated with poor outcome. Thus, STAT3 became an attractive therapeutic target but until now drugs targeting STAT3 only had moderate efficacy. This phenomenon might be related to the expression ratio of the two alternatively spliced isoforms: the full-length isoform STAT3α and the truncated version STAT3β, which play opposite roles in AML. In this study, we investigated the potential of selected, well-established drugs to impact the STAT3β/α ratio, as a higher STAT3β/α ratio is associated with better disease outcome. Atovaquone and selinexor independently elevated the STAT3β/α ratio and led to an upregulation of the STAT3β target gene SELL (CD62L). The combined treatment with atovaquone and selinexor entailed synergistic killing of AML cells in vitro and impaired the leukemic cell infiltration in vivo. Moreover, CD62L overexpression in a human AML cell line resulted in significantly prolonged survival in a xenograft mouse model. We propose that targeting the STAT3β/α ratio could be a promising new strategy for treating patients with AML and that the combination of selinexor and atovaquone could offer enhanced treatment outcomes.

Original languageEnglish
Article number217501
Pages (from-to)217501
JournalCancer Letters
Volume613
DOIs
Publication statusE-pub ahead of print - 24 Jan 2025

Fingerprint

Dive into the research topics of 'Atovaquone and selinexor as a novel combination treatment option in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this