2. Academic Validation
  3. 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.
PMID: 30504235 DOI: 10.1182/bloodadvances.2018016733
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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