1. Academic Validation
  2. The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy

The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy

  • Blood Adv. 2018 Dec 11;2(23):3428-3442. doi: 10.1182/bloodadvances.2018016733.
Suhu Liu 1 2 Anna E Marneth 3 Gabriela Alexe 4 Sarah R Walker 1 2 Helen I Gandler 1 Darwin Q Ye 1 Katherine Labella 1 Radhika Mathur 1 Patricia A Toniolo 1 Michelle Tillgren 5 Prafulla C Gokhale 5 David Barbie 1 2 Ann Mullally 1 2 3 6 Kimberly Stegmaier 4 David A Frank 1 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • 2 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
  • 3 Division of Hematology, Brigham and Women's Hospital, Boston, MA.
  • 4 Department of Pediatric Oncology and.
  • 5 Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, and.
  • 6 Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA.
Abstract

To identify novel therapeutic targets in acute myeloid leukemia (AML), we examined kinase expression patterns in primary AML samples. We found that the serine/threonine kinase IKBKE, a noncanonical IkB kinase, is expressed at higher levels in myeloid leukemia cells compared with normal hematopoietic cells. Inhibiting IKBKE, or its close homolog TANK-binding kinase 1 (TBK1), by either short hairpin RNA knockdown or pharmacological compounds, induces Apoptosis and reduces the viability of AML cells. Using gene expression profiling and gene set enrichment analysis, we found that IKBKE/TBK1-sensitive AML cells typically possess an MYC oncogenic signature. Consistent with this finding, the MYC oncoprotein was significantly downregulated upon IKBKE/TBK1 inhibition. Using proteomic analysis, we found that the oncogenic gene regulator YB-1 was activated by IKBKE/TBK1 through phosphorylation, and that YB-1 binds to the MYC promoter to enhance MYC gene transcription. Momelotinib (CYT387), a pharmacological inhibitor of IKBKE/TBK1, inhibits MYC expression, reduces viability and clonogenicity of primary AML cells, and demonstrates efficacy in a murine model of AML. Together, these data identify IKBKE/TBK1 as a promising therapeutic target in AML.

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