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Protein kinase C inhibitor Sotrastaurin selectively inhibits the growth of CD79-mutant diffuse large B-cell lymphomas

Item Type:Article
Title:Protein kinase C inhibitor Sotrastaurin selectively inhibits the growth of CD79-mutant diffuse large B-cell lymphomas
Creators Name:Naylor, T.L. and Tang, H. and Ratsch, B.A. and Enns, A. and Loo, A. and Chen, L. and Lenz, P. and Schuler, W. and Doerken, B. and Yao, Y.M. and Warmuth, M. and Lenz, G. and Stegmeier, F.
Abstract:The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis. The ABC subtype of DLBCL is associated with constitutive activation of the NF-kappaB pathway, and oncogenic lesions have been identified in its regulators, including CARD11/CARMA1 (caspase recruitment domain-containing protein 11), A20/TNFAIP3, and CD79A/B. In this study, we offer evidence of therapeutic potential for the selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in preclinical models of DLBCL. A significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to STN, and we found that the molecular nature of NF-kappaB pathway lesions predicted responsiveness. CD79A/B mutations correlated with STN sensitivity, whereas CARD11 mutations rendered ABC DLBCL cell lines insensitive. Growth inhibitory effects of PKC inhibition correlated with NF-kappaB pathway inhibition and were mediated by induction of G(1)-phase cell-cycle arrest and/or cell death. We found that STN produced significant antitumor effects in a mouse xenograft model of CD79A/B-mutated DLBCL. Collectively, our findings offer a strong rationale for the clinical evaluation of STN in ABC DLBCL patients who harbor CD79 mutations also illustrating the necessity to stratify DLBCL patients according to their genetic abnormalities.
Keywords:CARD Signaling Adaptor Proteins, CD79 Antigens, Cell Growth Processes, Diffuse Large B-Cell Lymphoma, G1 Phase, Guanylate Cyclase, Mutation, NF-kappa B, Protein Kinase C, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcr, Pyrroles, Quinazolines, Signal Transduction, Tumor Cell Line, Animals, Mice
Source:Cancer Research
Publisher:American Association for Cancer Research (U.S.A.)
Page Range:2643-2653
Date:1 April 2011
Official Publication:https://doi.org/10.1158/0008-5472.CAN-10-2525
PubMed:View item in PubMed

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