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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

PIM Kinase Inhibitors Block the Growth of Primary T-cell Acute Lymphoblastic Leukemia: Resistance Pathways Identified by Network Modeling Analysis

James T. Lim, Neha Singh, Libia A. Leuvano, Valerie S. Calvert, Emanuel F. Petricoin, David T. Teachey, Richard B. Lock, Megha Padi, Andrew S. Kraft and Sathish K.R. Padi
James T. Lim
1Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.
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Neha Singh
2University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
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Libia A. Leuvano
2University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
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Valerie S. Calvert
3Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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Emanuel F. Petricoin
3Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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David T. Teachey
4Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
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Richard B. Lock
5Children's Cancer Institute, School of Women's and Children's Health, UNSW Sydney, Sydney, Australia.
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Megha Padi
1Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona.
6Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, Arizona.
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Andrew S. Kraft
2University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
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  • For correspondence: sathishpadi@gmail.com akraft@uacc.arizona.edu
Sathish K.R. Padi
2University of Arizona Cancer Center, University of Arizona, Tucson, Arizona.
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  • For correspondence: sathishpadi@gmail.com akraft@uacc.arizona.edu
DOI: 10.1158/1535-7163.MCT-20-0160 Published September 2020
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Abstract

Despite significant progress in understanding the genetic landscape of T-cell acute lymphoblastic leukemia (T-ALL), the discovery of novel therapeutic targets has been difficult. Our results demonstrate that the levels of PIM1 protein kinase is elevated in early T-cell precursor ALL (ETP-ALL) but not in mature T-ALL primary samples. Small-molecule PIM inhibitor (PIMi) treatment decreases leukemia burden in ETP-ALL. However, treatment of animals carrying ETP-ALL with PIMi was not curative. To model other pathways that could be targeted to complement PIMi activity, HSB-2 cells, previously characterized as a PIMi-sensitive T-ALL cell line, were grown in increasing doses of PIMi. Gene set enrichment analysis of RNA sequencing data and functional enrichment of network modules demonstrated that the HOXA9, mTOR, MYC, NFκB, and PI3K-AKT pathways were activated in HSB-2 cells after long-term PIM inhibition. Reverse phase protein array–based pathway activation mapping demonstrated alterations in the mTOR, PI3K-AKT, and NFκB pathways, as well. PIMi-tolerant HSB-2 cells contained phosphorylated RelA-S536 consistent with activation of the NFκB pathway. The combination of NFκB and PIMis markedly reduced the proliferation in PIMi-resistant leukemic cells showing that this pathway plays an important role in driving the growth of T-ALL. Together these results demonstrate key pathways that are activated when HSB-2 cell line develop resistance to PIMi and suggest pathways that can be rationally targeted in combination with PIM kinases to inhibit T-ALL growth.

This article is featured in Highlights of This Issue, p. 1761

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1809–21

  • Received March 3, 2020.
  • Revision received April 27, 2020.
  • Accepted July 10, 2020.
  • Published first August 4, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (9)
September 2020
Volume 19, Issue 9
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PIM Kinase Inhibitors Block the Growth of Primary T-cell Acute Lymphoblastic Leukemia: Resistance Pathways Identified by Network Modeling Analysis
James T. Lim, Neha Singh, Libia A. Leuvano, Valerie S. Calvert, Emanuel F. Petricoin, David T. Teachey, Richard B. Lock, Megha Padi, Andrew S. Kraft and Sathish K.R. Padi
Mol Cancer Ther September 1 2020 (19) (9) 1809-1821; DOI: 10.1158/1535-7163.MCT-20-0160

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PIM Kinase Inhibitors Block the Growth of Primary T-cell Acute Lymphoblastic Leukemia: Resistance Pathways Identified by Network Modeling Analysis
James T. Lim, Neha Singh, Libia A. Leuvano, Valerie S. Calvert, Emanuel F. Petricoin, David T. Teachey, Richard B. Lock, Megha Padi, Andrew S. Kraft and Sathish K.R. Padi
Mol Cancer Ther September 1 2020 (19) (9) 1809-1821; DOI: 10.1158/1535-7163.MCT-20-0160
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Molecular Cancer Therapeutics
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