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

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 Chang, Jeffrey Tyner, Michael P. Vitek, María D. Odero, Rosalie Sears, Anupriya Agarwal

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)84214-84227
Number of pages14
JournalOncotarget
Volume7
Issue number51
DOIs
StatePublished - 2016

Fingerprint

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Protein-Tyrosine Kinases
Protein Phosphatase 2
Cell Line
Phosphotransferases
Therapeutics
Phosphoprotein Phosphatases
Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Phosphoric Monoester Hydrolases
Tyrosine
Catalytic Domain
Neoplasms
Cell Survival
T-Lymphocytes
Growth

Keywords

  • C-MYC
  • PP2A
  • SET
  • T-ALL
  • Tyrosine kinases

ASJC Scopus subject areas

  • Oncology

Cite this

Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia. / Richard, Nameeta P.; Pippa, Raffaella; Cleary, Megan M.; Puri, Alka; Tibbitts, Deanne; Mahmood, Shawn; Christensen, Dale J.; Jeng, Sophia; McWeeney, Shannon; Look, A. Thomas; Chang, Bill; Tyner, Jeffrey; Vitek, Michael P.; Odero, María D.; Sears, Rosalie; Agarwal, Anupriya.

In: Oncotarget, Vol. 7, No. 51, 2016, p. 84214-84227.

Research output: Contribution to journalArticle

Richard, NP, Pippa, R, Cleary, MM, Puri, A, Tibbitts, D, Mahmood, S, Christensen, DJ, Jeng, S, McWeeney, S, Look, AT, Chang, B, Tyner, J, Vitek, MP, Odero, MD, Sears, R & Agarwal, A 2016, 'Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia', Oncotarget, vol. 7, no. 51, pp. 84214-84227. https://doi.org/10.18632/oncotarget.12394
Richard, Nameeta P. ; Pippa, Raffaella ; Cleary, Megan M. ; Puri, Alka ; Tibbitts, Deanne ; Mahmood, Shawn ; Christensen, Dale J. ; Jeng, Sophia ; McWeeney, Shannon ; Look, A. Thomas ; Chang, Bill ; Tyner, Jeffrey ; Vitek, Michael P. ; Odero, María D. ; Sears, Rosalie ; Agarwal, Anupriya. / Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia. In: Oncotarget. 2016 ; Vol. 7, No. 51. pp. 84214-84227.
@article{8f13d5938d6d482db8addf3a364bb3ba,
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.",
keywords = "C-MYC, PP2A, SET, T-ALL, Tyrosine kinases",
author = "Richard, {Nameeta P.} and Raffaella Pippa and Cleary, {Megan M.} and Alka Puri and Deanne Tibbitts and Shawn Mahmood and Christensen, {Dale J.} and Sophia Jeng and Shannon McWeeney and Look, {A. Thomas} and Bill Chang and Jeffrey Tyner and Vitek, {Michael P.} and Odero, {Mar{\'i}a D.} and Rosalie Sears and Anupriya Agarwal",
year = "2016",
doi = "10.18632/oncotarget.12394",
language = "English (US)",
volume = "7",
pages = "84214--84227",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "51",

}

TY - JOUR

T1 - Combined targeting of SET and tyrosine kinases provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia

AU - Richard, Nameeta P.

AU - Pippa, Raffaella

AU - Cleary, Megan M.

AU - Puri, Alka

AU - Tibbitts, Deanne

AU - Mahmood, Shawn

AU - Christensen, Dale J.

AU - Jeng, Sophia

AU - McWeeney, Shannon

AU - Look, A. Thomas

AU - Chang, Bill

AU - Tyner, Jeffrey

AU - Vitek, Michael P.

AU - Odero, María D.

AU - Sears, Rosalie

AU - Agarwal, Anupriya

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - C-MYC

KW - PP2A

KW - SET

KW - T-ALL

KW - Tyrosine kinases

UR - http://www.scopus.com/inward/record.url?scp=85007414124&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007414124&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.12394

DO - 10.18632/oncotarget.12394

M3 - Article

C2 - 27705940

AN - SCOPUS:85007414124

VL - 7

SP - 84214

EP - 84227

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 51

ER -