MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia

• Published in: Leukemia Vol. 30; no. 9; pp. 1832 - 1843
• Main Authors: Canté-Barrett, K, Spijkers-Hagelstein, J A P, Buijs-Gladdines, J G C A M, Uitdehaag, J C M, Smits, W K, van der Zwet, J, Buijsman, R C, Zaman, G J R, Pieters, R, Meijerink, J P P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-09-2016; Nature Publishing Group
• Subjects: 13/106; 13/109; 42/44; 45/23; 631/67/1990/283/2125; 631/67/68; 631/80/86; 96; 96/95; Acute lymphocytic leukemia; Animals; B cells; Cancer Research; Cell cycle; Cell Proliferation - drug effects; Critical Care Medicine; Cytotoxicity; Genes; Genetic aspects; Hematology; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Lymphoma; Medicine; Medicine & Public Health; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mutation; Oncology; Original; original-article; Patients; Pediatrics; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Receptors, Interleukin-7 - antagonists & inhibitors; Receptors, Interleukin-7 - metabolism; Signal Transduction - drug effects; T cells; Transfection; Tumor Cells, Cultured; Netherlands
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.83

We identified mutations in the
IL7Ra
gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules—but not their wild-type counterparts—rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.