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Signal Transduction and Functional Imaging

Preclinical Evaluation of Gilteritinib on NPM1-ALK–Driven Anaplastic Large Cell Lymphoma Cells

Sudhakiranmayi Kuravi, Janice Cheng, Gabrielle Fangman, Kishore Polireddy, Sophia McCormick, Tara L. Lin, Anurag K. Singh, Sunil Abhyankar, Siddhartha Ganguly, Danny R. Welch, Roy A. Jensen, Joseph P. McGuirk and Ramesh Balusu
Sudhakiranmayi Kuravi
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Janice Cheng
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Gabrielle Fangman
2The University of Kansas Medical School, Kansas City, Kansas.
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Kishore Polireddy
3Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
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Sophia McCormick
4Biospecimen Repository Core Facility, University of Kansas Medical Center, Kansas City, Kansas.
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Tara L. Lin
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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  • ORCID record for Tara L. Lin
Anurag K. Singh
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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Sunil Abhyankar
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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Siddhartha Ganguly
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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Danny R. Welch
5The University of Kansas Cancer Center, Kansas City, Kansas.
6Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
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Roy A. Jensen
5The University of Kansas Cancer Center, Kansas City, Kansas.
7Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Joseph P. McGuirk
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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Ramesh Balusu
1Division of Hematologic Malignancies and Cellular Therapeutics, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
5The University of Kansas Cancer Center, Kansas City, Kansas.
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  • For correspondence: rbalusu@kumc.edu
DOI: 10.1158/1541-7786.MCR-20-0738
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Abstract

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the nucleophosmin 1 (NPM1)-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream signaling pathways responsible for lymphoma cell proliferation and survival. Gilteritinib is a tyrosine kinase inhibitor recently approved by the FDA for the treatment of FMS-like tyrosine kinase mutation–positive acute myeloid leukemia. In this study, we demonstrate for the first time gilteritinib-mediated growth inhibitory effects on NPM1-ALK–driven ALCL cells. We utilized a total of five ALCL model cell lines, including both human and murine. Gilteritinib treatment inhibits NPM1-ALK fusion kinase phosphorylation and downstream signaling, resulting in induced apoptosis. Gilteritinib-mediated apoptosis was associated with caspase 3/9, PARP cleavage, the increased expression of proapoptotic protein BAD, and decreased expression of antiapoptotic proteins, survivin and MCL-1. We also found downregulation of fusion kinase activity resulted in decreased c-Myc protein levels. Furthermore, cell-cycle analysis indicated gilteritinib induced G0–G1-phase cell-cycle arrest and reduced CD30 expression. In summary, our preclinical studies explored the novel therapeutic potential of gilteritinib in the treatment of ALCL cells expressing NPM1-ALK and potentially in other ALK or ALK fusion–driven hematologic or solid malignancies.

Implications: Our preclinical results explore the use of gilteritinib for the treatment of NPM1-ALK–driven ALCL cells and pave a path for developing future clinical trials.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/00/0/000/F1.large.jpg.

Footnotes

  • Mol Cancer Res 2021;XX:XX–XX

  • Received August 29, 2020.
  • Revision received December 14, 2020.
  • Accepted January 22, 2021.
  • Published first January 29, 2021.
  • ©2021 American Association for Cancer Research.

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This OnlineFirst version was published on February 24, 2021
doi: 10.1158/1541-7786.MCR-20-0738

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Preclinical Evaluation of Gilteritinib on NPM1-ALK–Driven Anaplastic Large Cell Lymphoma Cells
Sudhakiranmayi Kuravi, Janice Cheng, Gabrielle Fangman, Kishore Polireddy, Sophia McCormick, Tara L. Lin, Anurag K. Singh, Sunil Abhyankar, Siddhartha Ganguly, Danny R. Welch, Roy A. Jensen, Joseph P. McGuirk and Ramesh Balusu
Mol Cancer Res February 24 2021 DOI: 10.1158/1541-7786.MCR-20-0738

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Preclinical Evaluation of Gilteritinib on NPM1-ALK–Driven Anaplastic Large Cell Lymphoma Cells
Sudhakiranmayi Kuravi, Janice Cheng, Gabrielle Fangman, Kishore Polireddy, Sophia McCormick, Tara L. Lin, Anurag K. Singh, Sunil Abhyankar, Siddhartha Ganguly, Danny R. Welch, Roy A. Jensen, Joseph P. McGuirk and Ramesh Balusu
Mol Cancer Res February 24 2021 DOI: 10.1158/1541-7786.MCR-20-0738
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