title: Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.
abstract: Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.
authors.affiliation: Randall Children's Hospital at Legacy Emanuel, Children's Cancer and Blood Disorders Program, Portland, OR 97227, USA.|Division of Pediatric Hematology Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Nameeta P
authors.initials: NP
authors.lastname: Richard
authors.affiliation: Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Pippa
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Cleary
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Puri
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Deanne
authors.initials: D
authors.lastname: Tibbitts
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Mahmood
authors.affiliation: Research and Development, Oncotide Pharmaceuticals, Research Triangle Park, NC 27710, USA .|Spyryx Biosciences, Durham, NC 27713, USA.
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.affiliation: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.affiliation: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.affiliation: Dana-Farber Cancer Institute, Harvard Cancer Center, Boston, MA 02215, USA.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.affiliation: Division of Pediatric Hematology Oncology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239, USA.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Research and Development, Oncotide Pharmaceuticals, Research Triangle Park, NC 27710, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.affiliation: Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
authors.forename: María D
authors.initials: MD
authors.lastname: Odero
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR USA-97239.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA-97239.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sears
authors.affiliation: Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA-97239.|Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR USA-97239.|Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA-97239.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Agarwal
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002648:Child; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056488:Histone Chaperones / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D010455:Peptides / Q000008:administration & dosage; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056488:Histone Chaperones; C583613:OP449 peptide; D010455:Peptides; D015363:Quinolones; C513473:SET protein, human; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; D054648:Protein Phosphatase 2
keywords: PP2A; SET; T-ALL; c-MYC; tyrosine kinases