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

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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., Tang, H., Ratsch, B.A., Enns, A., Loo, A., Chen, L., Lenz, P., Schuler, W., Doerken, B., Yao, Y.M., Warmuth, M., 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
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	71
Number:	7
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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