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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lin, KH; Rutter, JC; Xie, A; Killarney, ST; Vaganay, C; Benaksas, C; Ling, F; Sodaro, G; Meslin, P-A; Bassil, CF; Fenouille, N; Hoj, J; Washart, R; Ang, HX; Cerda-Smith, C; Chaintreuil, P; Jacquel, A; Auberger, P; Forget, A; Itzykson, R; Lu, M; Lin, J; Pierobon, M; Sheng, Z; Li, X; Chilkoti, A; Owzar, K; Rizzieri, DA; Pardee, TS; Benajiba, L; Petricoin, E; Puissant, A; Wood, KC

Published Date

  • July 2022

Published In

Volume / Issue

  • 3 / 7

Start / End Page

  • 837 - 851

PubMed ID

  • 35668193

Electronic International Standard Serial Number (EISSN)

  • 2662-1347

Digital Object Identifier (DOI)

  • 10.1038/s43018-022-00394-x

Language

  • eng

Conference Location

  • England