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

• Published in: Cell reports (Cambridge) Vol. 40; no. 6; p. 111177
• Main Authors: Emdal, Kristina B., Palacio-Escat, Nicolàs, Wigerup, Caroline, Eguchi, Akihiro, Nilsson, Helén, Bekker-Jensen, Dorte B., Rönnstrand, Lars, Kazi, Julhash U., Puissant, Alexandre, Itzykson, Raphaël, Saez-Rodriguez, Julio, Masson, Kristina, Blume-Jensen, Peter, Olsen, Jesper V.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 09.08.2022; Cell Press
• Subjects: acute myeloid leukemia; Basic Medicine; Cell and Molecular Biology; Cell- och molekylärbiologi; combination therapy; CP: Cancer; CP: Molecular biology; drug resistance; functional scoring; mass spectrometry; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; MK-2206; nutlin-3a; phosphoproteomics; selinexor; subcellular proteomics; phosphoproteomics; acute myeloid leukemia; selinexor; CP: Cancer; CP: Molecular biology; mass spectrometry; combination therapy; MK-2206; functional scoring; drug resistance; subcellular proteomics; nutlin-3a
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111177

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. [Display omitted] •Phosphoproteomics with functional scoring uncovers context for selinexor sensitivity•Functional p53 correlates with selinexor sensitivity, which is enhanced by nutlin-3a•Dysregulated AKT-FOXO3 drives selinexor resistance, which is overcome with MK-2206•Spatial proteomics reveals selinexor-induced nucleocytoplasmic protein shuttling Emdal et al. combine phosphoproteomics of samples from patients with AML and functional phosphosite scoring to uncover clinically actionable molecular context for selinexor efficacy. Sensitivity to selinexor correlates with functional p53 and is enhanced with nutlin-3a, while resistance is associated with dysregulated AKT-FOXO3 signaling and overcome by combining with MK-2206.