Signaling network diversification during differentiation sensitizes AML cells to PAK and MEK inhibitors

ABSTRACT: A main requirement for precision medicine is the identification of patients that are more likely to respond to a particular drug. AML is a heterogeneous disease in which molecules associated to kinase signaling are frequently mutated. However, no kinase inhibitor has been approved for the treatment of this malignancy. Thus, patient stratification requires new molecular profiling techniques in addition of to the current sequencing strategies. We have used a multiomics approach that combines proteomics, phosphoproteomics, mass cytometry and DNA sequencing to classify primary AML cells derived from 36 patients. Comprehensive integrative analysis identified molecular signatures based on phosphopeptide abundance or surface marker expression that separate AML cases according to their differentiation status. Differentiated cells presented a particular pattern of protein phosphorylation, an enrichment in the activity of several kinases and a higher sensitivity to PAK, MEK and PKC/FLT3 inhibitors. In addition, mutations in proteins closely linked to kinase signaling were more frequent on differentiated cells. Interestingly the set of patients with differentiated cells as clustered by marker expression signatures showed an increased overall survival in our set of patients and in the TCGA database registered cohort. Thus, molecular differentiation signatures could be used as prognosis and drug response markers in order to implement the application of precision medicine in AML patients.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Pedro Casado-Izquierdo  

LAB HEAD: Pedro R. Cutillas

PROVIDER: PXD005978 | Pride | 2020-04-15

REPOSITORIES: Pride