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, Ramesh Balusu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 gilteritinibmediated growth inhibitory effects on NPM1-ALK-driven ALCL cells. Weutilized 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.

Original languageEnglish (US)
Pages (from-to)913-920
Number of pages8
JournalMolecular Cancer Research
Volume19
Issue number5
DOIs
StatePublished - May 1 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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