title: MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Canté-Barrett
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: J A P
authors.initials: JA
authors.lastname: Spijkers-Hagelstein
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J G C A M
authors.initials: JG
authors.lastname: Buijs-Gladdines
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: J C M
authors.initials: JC
authors.lastname: Uitdehaag
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: W K
authors.initials: WK
authors.lastname: Smits
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van der Zwet
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: R C
authors.initials: RC
authors.lastname: Buijsman
authors.affiliation: Netherlands Translational Research Center B.V., Oss, The Netherlands.
authors.forename: G J R
authors.initials: GJ
authors.lastname: Zaman
authors.affiliation: The Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D020395:Receptors, Interleukin-7; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases