PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

Dalia El-Gamal, Katie Williams, Taylor D. LaFollette, Matthew Cannon, James S. Blachly, Yiming Zhong, Jennifer A. Woyach, Erich Williams, Farrukh T. Awan, Jeffrey Jones, Leslie Andritsos, Kami Maddocks, Chia Hsien Wu, Ching Shih Chen, Amy Lehman, Xiaoli Zhang, Rosa Lapalombella, John C. Byrd

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 asmonotherapy in clinical trials of relapsed and refractory CLL patients are warranted.

Original languageEnglish (US)
Pages (from-to)1481-1491
Number of pages11
JournalBlood
Volume124
Issue number9
DOIs
StatePublished - Aug 28 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    El-Gamal, D., Williams, K., LaFollette, T. D., Cannon, M., Blachly, J. S., Zhong, Y., Woyach, J. A., Williams, E., Awan, F. T., Jones, J., Andritsos, L., Maddocks, K., Wu, C. H., Chen, C. S., Lehman, A., Zhang, X., Lapalombella, R., & Byrd, J. C. (2014). PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL. Blood, 124(9), 1481-1491. https://doi.org/10.1182/blood-2014-05-574830