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

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

doi:10.1038/s43018-022-00394-x

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

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 ItzyksonMin 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English
Pages (from-to)	837-851
Number of pages	15
Journal	Nature Cancer
Volume	3
Issue number	7
DOIs	https://doi.org/10.1038/s43018-022-00394-x
State	Published - Jul 2022
Externally published	Yes

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Lin, K. H., Rutter, J. C., Xie, A., Killarney, S. T., Vaganay, C., Benaksas, C., Ling, F., Sodaro, G., Meslin, P. A., Bassil, C. F., Fenouille, N., Hoj, J., Washart, R., Ang, H. X., Cerda-Smith, C., Chaintreuil, P., Jacquel, A., Auberger, P., Forget, A., ... Wood, K. C. (2022). P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nature Cancer, 3(7), 837-851. https://doi.org/10.1038/s43018-022-00394-x

@article{d0fbd819283240b89f50036cd621ee00,

title = "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{\textquoteright}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.",

author = "Lin, {Kevin H.} and Rutter, {Justine C.} and Abigail Xie and Killarney, {Shane T.} and Camille Vaganay and Chaima Benaksas and Frank Ling and Gaetano Sodaro and Meslin, {Paul Arthur} and Bassil, {Christopher F.} and Nina Fenouille and Jacob Hoj and Rachel Washart and Ang, {Hazel X.} and Christian Cerda-Smith and Paul Chaintreuil and Arnaud Jacquel and Patrick Auberger and Antoine Forget and Raphael Itzykson and Min Lu and Jiaxing Lin and Mariaelena Pierobon and Zhecheng Sheng and Xinghai Li and Ashutosh Chilkoti and Kouros Owzar and Rizzieri, {David A.} and Pardee, {Timothy S.} and Lina Benajiba and Emanuel Petricoin and Alexandre Puissant and Wood, {Kris C.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = jul,

doi = "10.1038/s43018-022-00394-x",

language = "English",

volume = "3",

pages = "837--851",

journal = "Nature Cancer",

issn = "2662-1347",

number = "7",

}

Lin, KH, Rutter, JC, Xie, A, Killarney, ST, Vaganay, C, Benaksas, C, Ling, F, Sodaro, G, Meslin, PA, 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 2022, 'P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia', Nature Cancer, vol. 3, no. 7, pp. 837-851. https://doi.org/10.1038/s43018-022-00394-x

TY - JOUR

T1 - P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia

AU - Lin, Kevin H.

AU - Rutter, Justine C.

AU - Xie, Abigail

AU - Killarney, Shane T.

AU - Vaganay, Camille

AU - Benaksas, Chaima

AU - Ling, Frank

AU - Sodaro, Gaetano

AU - Meslin, Paul Arthur

AU - Bassil, Christopher F.

AU - Fenouille, Nina

AU - Hoj, Jacob

AU - Washart, Rachel

AU - Ang, Hazel X.

AU - Cerda-Smith, Christian

AU - Chaintreuil, Paul

AU - Jacquel, Arnaud

AU - Auberger, Patrick

AU - Forget, Antoine

AU - Itzykson, Raphael

AU - Lu, Min

AU - Lin, Jiaxing

AU - Pierobon, Mariaelena

AU - Sheng, Zhecheng

AU - Li, Xinghai

AU - Chilkoti, Ashutosh

AU - Owzar, Kouros

AU - Rizzieri, David A.

AU - Pardee, Timothy S.

AU - Benajiba, Lina

AU - Petricoin, Emanuel

AU - Puissant, Alexandre

AU - Wood, Kris C.

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

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U2 - 10.1038/s43018-022-00394-x

DO - 10.1038/s43018-022-00394-x

M3 - Article

C2 - 35668193

AN - SCOPUS:85131524204

SN - 2662-1347

VL - 3

SP - 837

EP - 851

JO - Nature Cancer

JF - Nature Cancer

IS - 7

ER -

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

Abstract

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