P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia

Area of Science:

• Molecular Oncology
• Cancer Therapeutics
• Hematologic Malignancies

Background:

• Selinexor is an FDA-approved XPO1 inhibitor for multiple myeloma and diffuse large B-cell lymphoma.
• Selinexor demonstrates promising activity in relapsed/refractory acute myeloid leukemia (AML), indicating potential for combination therapies.
• The effects of selinexor on AML cell fitness are complex, involving nuclear sequestration of various substrates.

Purpose of the Study:

• To systematically identify the pro- and anti-fitness effects of selinexor in AML.
• To investigate the molecular mechanisms underlying selinexor's impact on AML cell signaling.
• To explore novel combination strategies to enhance selinexor's therapeutic efficacy in AML.

Main Methods:

• Systematic cataloging of selinexor's effects on AML cell fitness.
• Analysis of PI3Kγ-dependent AKT signaling activation.
• Upregulation of the purinergic receptor P2RY2.
• Inhibition of the P2RY2-AKT axis in AML cell lines, patient-derived primary cultures, and mouse models.
• Evaluation of selinexor and ipatasertib combination therapy in an MLL-AF9-driven AML mouse model.

Main Results:

• Selinexor treatment upregulates the purinergic receptor P2RY2, activating PI3Kγ-dependent AKT signaling in AML cells.
• Inhibition of the P2RY2-AKT signaling axis potentiates selinexor's anti-leukemic effects.
• Combination therapy with selinexor and ipatasertib demonstrated superior efficacy compared to standard chemotherapy in an AML mouse model.

Conclusions:

• Drug-induced P2RY2-AKT signaling is an actionable consequence of XPO1 inhibition in AML.
• Targeting this pathway offers a promising strategy to overcome resistance and enhance selinexor's efficacy in AML.
• Selinexor-based combination therapies, particularly with PI3K inhibitors, hold significant clinical potential for AML treatment.