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: Nameeta P Richard, Raffaella Pippa, Megan M Cleary, Alka Puri, Deanne Tibbitts, Shawn Mahmood, Dale J Christensen, Sophia Jeng, Shannon McWeeney, A Thomas Look, Bill H Chang, Jeffrey W Tyner, Michael P Vitek, María D Odero, Rosalie Sears, Anupriya Agarwal
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 51 Pg. 84214-84227 (Dec 20 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27705940 (Publication Type: Journal Article)

Chemical References

• 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
• Benzimidazoles
• DNA-Binding Proteins
• Enzyme Inhibitors
• Histone Chaperones
• OP449 peptide
• Peptides
• Quinolones
• SET protein, human
• Transcription Factors
• Protein-Tyrosine Kinases
• Protein Phosphatase 2

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Benzimidazoles (administration & dosage)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Child
• DNA-Binding Proteins
• Enzyme Inhibitors (administration & dosage)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Chaperones (antagonists & inhibitors, genetics, metabolism)
• Humans
• Jurkat Cells
• Male
• Peptides (administration & dosage)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Protein Phosphatase 2 (antagonists & inhibitors, genetics, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Quinolones (administration & dosage)
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Young Adult