期刊
NATURE CANCER
卷 3, 期 7, 页码 837-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-022-00394-x
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资金
- Duke University School of Medicine start-up funds
- Duke Cancer Institute
- National Institutes of Health [R01CA207083, F30CA206348, K00CA245732-04, F30CA247323]
- Duke Medical Scientist Training Program [T32 GM007171]
- Duke Undergraduate Research Support Office
- Agency for Science, Technology and Research, Singapore
- ATIP/AVENIR French research program
- ERC Starting program [758848]
- EHA research grant for Non-Clinical Advanced Fellow
- FSER association
- St Louis Association for leukemia research
- European Research Council (ERC) [758848] Funding Source: European Research Council (ERC)
The XPO1 inhibitor Selinexor activates PI3Ky-dependent AKT signaling in AML via upregulation of P2RY2, leading to positive antileukemic effects. Inhibiting this signaling pathway enhances the efficacy of Selinexor in AML.
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 PI3K gamma-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. Wood and colleagues report that the XPO1 inhibitor selinexor activates PI3Ky-dependent AKT signaling in AML via upregulation of P2RY2 and demonstrate a synergistic effect of combining selinexor with inhibition of prosurvival AKT signaling.
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