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

Abstract

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.

• Authors: Kevin H Lin, Justine C Rutter, Abigail Xie, Shane T Killarney, Camille Vaganay, Chaima Benaksas, Frank Ling, Gaetano Sodaro, Paul-Arthur Meslin, Christopher F Bassil, Nina Fenouille, Jacob Hoj, Rachel Washart, Hazel X Ang, Christian Cerda-Smith, Paul Chaintreuil, Arnaud Jacquel, Patrick Auberger, Antoine Forget, Raphael Itzykson, Min Lu, Jiaxing Lin, Mariaelena Pierobon, Zhecheng Sheng, Xinghai Li, Ashutosh Chilkoti, Kouros Owzar, David A Rizzieri, Timothy S Pardee, Lina Benajiba, Emanuel Petricoin, Alexandre Puissant, Kris C Wood
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 7 Pg. 837-851 (07 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 35668193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• Karyopherins
• P2ry2 protein, mouse
• Receptors, Cytoplasmic and Nuclear
• Receptors, Purinergic P2Y2
• exportin 1 protein
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Karyopherins (antagonists & inhibitors)
• Leukemia, Myeloid, Acute (drug therapy)
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• Receptors, Purinergic P2Y2 (metabolism)
• United States