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

Publication ,  Journal Article
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; Lu, M ...
Published in: Nat Cancer
July 2022

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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Published In

Nat Cancer

DOI

EISSN

2662-1347

Publication Date

July 2022

Volume

3

Issue

7

Start / End Page

837 / 851

Location

England

Related Subject Headings

  • United States
  • Receptors, Purinergic P2Y2
  • Receptors, Cytoplasmic and Nuclear
  • Proto-Oncogene Proteins c-akt
  • Mice
  • Leukemia, Myeloid, Acute
  • Karyopherins
  • Exportin 1 Protein
  • Antineoplastic Combined Chemotherapy Protocols
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lin, K. H., Rutter, J. C., Xie, A., Killarney, S. T., Vaganay, C., Benaksas, C., … Wood, K. C. (2022). P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nat Cancer, 3(7), 837–851. https://doi.org/10.1038/s43018-022-00394-x
Lin, Kevin H., Justine C. Rutter, Abigail Xie, Shane T. Killarney, Camille Vaganay, Chaima Benaksas, Frank Ling, et al. “P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.Nat Cancer 3, no. 7 (July 2022): 837–51. https://doi.org/10.1038/s43018-022-00394-x.
Lin KH, Rutter JC, Xie A, Killarney ST, Vaganay C, Benaksas C, et al. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nat Cancer. 2022 Jul;3(7):837–51.
Lin, Kevin H., et al. “P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.Nat Cancer, vol. 3, no. 7, July 2022, pp. 837–51. Pubmed, doi:10.1038/s43018-022-00394-x.
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. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nat Cancer. 2022 Jul;3(7):837–851.

Published In

Nat Cancer

DOI

EISSN

2662-1347

Publication Date

July 2022

Volume

3

Issue

7

Start / End Page

837 / 851

Location

England

Related Subject Headings

  • United States
  • Receptors, Purinergic P2Y2
  • Receptors, Cytoplasmic and Nuclear
  • Proto-Oncogene Proteins c-akt
  • Mice
  • Leukemia, Myeloid, Acute
  • Karyopherins
  • Exportin 1 Protein
  • Antineoplastic Combined Chemotherapy Protocols
  • Animals