Oncotarget

Research Papers:

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

Sathish K.R. Padi, Libia A. Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H. Song, Jon C. Aster, Xue-Zhong Yu, Shikhar Mehrotra and Andrew S. Kraft _

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Oncotarget. 2017; 8:30199-30216. https://doi.org/10.18632/oncotarget.16320

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Abstract

Sathish K.R. Padi1, Libia A. Luevano1, Ningfei An2, Ritu Pandey1,3, Neha Singh1, Jin H. Song1,3, Jon C. Aster4, Xue-Zhong Yu5, Shikhar Mehrotra6, Andrew S. Kraft1

1University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

2Department of Pathology, Pediatric Hematology/Oncology Division, University of Chicago, Chicago, IL, USA

3Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

4Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

5Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

6Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

Correspondence to:

Andrew S. Kraft, email: akraft@uacc.arizona.edu

Keywords: PIM kinase, T-ALL, ETP-ALL, tyrosine kinase inhibitor, ponatinib

Received: October 15, 2016     Accepted: March 08, 2017     Published: March 17, 2017

ABSTRACT

New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.


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