Phosphoproteomic Profiling of T-Cell Acute Lymphoblastic Leukemia Identifies Targetable Kinases and Combination Treatments

Protein kinase inhibitors are amongst the most successful cancer treatments, but targetable kinases activated by gene fusions are rare in T-ALL (e.g., NUP214-ABL1). Nevertheless, leukemic blasts rely on enhanced kinase signaling to sustain dysregulated proliferation. Protein kinases can be hyper-activated in the absence of defects in their genes. Thus, phospho-proteomics can provide information on pathway activation, signaling networks and aberrant kinases activities that offer important opportunities for targeted therapies. Here, we performed mass spectrometry-based global profiling of tyrosine, serine, and threonine phosphorylation in a panel of 11 T-ALL cell lines to identify potential targetable kinases. We report a comprehensive dataset consisting of 21,000 phosphosites on 4896 phosphoproteins, including 217 kinases. We identify several Src-family members (LCK, SRC, FYN, YES1) as well as the cyclin-dependent kinases CDK1 and CDK2 as broadly activated in our panel. We validate highly active kinases as putative target for therapy in vitro and propose potential novel combination treatment strategies, such as the inhibition of the insulin-like growth factor receptor (IGF-1R) signaling pathway to increase the sensitivity to dasatinib treatment in T-ALL.