TY - JOUR

T1 - Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance

AU - Emdal, Kristina Bennet

AU - Palacio-Escat, Nicolàs

AU - Wigerup, Caroline

AU - Eguchi, Akihiro

AU - Nilsson, Helén

AU - Bekker-Jensen, Dorte B.

AU - Rönnstrand, Lars

AU - Kazi, Julhash U

AU - Puissant, Alexandre

AU - Itzykson, Raphaël

AU - Saez-Rodriguez, Julio

AU - Masson, Kristina

AU - Blume-Jensen, Peter

AU - Olsen, Jesper Velgaard

N1 - Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2022

Y1 - 2022

N2 - Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.

AB - Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.

KW - Apoptosis

KW - Cell Line, Tumor

KW - Humans

KW - Hydrazines

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Proteome/metabolism

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Triazoles

KW - Tumor Suppressor Protein p53/metabolism

U2 - 10.1016/j.celrep.2022.111177

DO - 10.1016/j.celrep.2022.111177

M3 - Journal article

C2 - 35947955

VL - 40

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 6

M1 - 111177

ER -