Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia
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Nameeta P. Richard1,7, Raffaella Pippa2, Megan M. Cleary3,10, Alka Puri3,10, Deanne Tibbitts4, Shawn Mahmood3,10, Dale J. Christensen5,11, Sophia Jeng6,10, Shannon McWeeney6,10, A. Thomas Look8, Bill H. Chang7,10, Jeffrey W. Tyner9,10, Michael P. Vitek5, María D. Odero2, Rosalie Sears4,10, Anupriya Agarwal3,4,10
1Randall Children’s Hospital at Legacy Emanuel, Children’s Cancer and Blood Disorders Program, Portland, OR USA-97227
2Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pio XII-55 Pamplona, Spain-31008
3Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA-97239
4Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR USA-97239
5Research and Development, Oncotide Pharmaceuticals, Research Triangle Park, NC USA 27710
6Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, 97239, USA
7Division of Pediatric Hematology Oncology, Oregon Health and Science University, Portland, OR, USA-97239
8Dana-Farber Cancer Institute, Harvard Cancer Center, Boston, MA, USA 02215
9Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR, USA-97239
10Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA-97239
11Spyryx Biosciences, Durham, NC USA-27713
Anupriya Agarwal, email: [email protected]
Keywords: T-ALL, c-MYC, SET, PP2A, tyrosine kinases
Received: February 26, 2016 Accepted: September 24, 2016 Published: October 01, 2016
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.
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