Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Richard, NP; Pippa, R; Cleary, MM; Puri, A; Tibbitts, D; Mahmood, S; Christensen, DJ; Jeng, S; McWeeney, S; Look, AT; Chang, BH; Tyner, JW; Vitek, MP; Odero, MD; Sears, R; Agarwal, A

Published Date

  • December 2016

Published In

Volume / Issue

  • 7 / 51

Start / End Page

  • 84214 - 84227

PubMed ID

  • 27705940

Pubmed Central ID

  • 27705940

Electronic International Standard Serial Number (EISSN)

  • 1949-2553

International Standard Serial Number (ISSN)

  • 1949-2553

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.12394

Language

  • eng