Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma

Wei Liu, Juan Chen, Archito T. Tamayo, Changgeng Ruan, Li Li, Shouhao Zhou, Chan Shen, Ken H. Young, Jason Westin, Richard E. Davis, Shimin Hu, Leonard J. Medeiros, Richard J. Ford, Lan V. Pham

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations. Ixazomib sensitivity in DLBCL cells is correlated with immunoproteasomal activity; stimulating lymphoma cells with interferon gamma induced immunoproteasome activity and sensitized these cells to ixazomib. In addition, we showed that ixazomib induces apoptosis and the DNA damage response pathway, through activation of the checkpoint kinase 2 (CHK2). Hence, pharmacological inhibition of CHK2 enhances the anti-tumor activity of ixazomib in DLBCL cells. Our results indicate that ixazomib is an effective proteasome inhibitor active in DLBCL, including DHL, and its combination with a CHK2 inhibitor offers a potentially more robust therapeutic regimen for treatment-resistant DLBCL.

Original languageEnglish (US)
Pages (from-to)346-360
Number of pages15
JournalOncotarget
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2018

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Liu, W., Chen, J., Tamayo, A. T., Ruan, C., Li, L., Zhou, S., Shen, C., Young, K. H., Westin, J., Davis, R. E., Hu, S., Medeiros, L. J., Ford, R. J., & Pham, L. V. (2018). Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma. Oncotarget, 9(1), 346-360. https://doi.org/10.18632/oncotarget.20378