OSU-T315: A novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells

Ta Ming Liu, Yonghua Ling, Jennifer A. Woyach, Kyle Beckwith, Yuh Ying Yeh, Erin Hertlein, Xiaoli Zhang, Amy Lehman, Farrukh Awan, Jeffrey A. Jones, Leslie A. Andritsos, Kami Maddocks, Jessica MacMurray, Santosh B. Salunke, Ching Shih Chen, Mitch A. Phelps, John C. Byrd, Amy J. Johnson

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo,OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1mousemodel. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.

Original languageEnglish (US)
Pages (from-to)284-295
Number of pages12
JournalBlood
Volume125
Issue number2
DOIs
StatePublished - Aug 8 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Liu, T. M., Ling, Y., Woyach, J. A., Beckwith, K., Yeh, Y. Y., Hertlein, E., Zhang, X., Lehman, A., Awan, F., Jones, J. A., Andritsos, L. A., Maddocks, K., MacMurray, J., Salunke, S. B., Chen, C. S., Phelps, M. A., Byrd, J. C., & Johnson, A. J. (2015). OSU-T315: A novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells. Blood, 125(2), 284-295. https://doi.org/10.1182/blood-2014-06-583518