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-κB 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-κB 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-κB pathway inhibition and were mediated by induction of G₁-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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Naylor TL,Tang H,Ratsch BA,Enns A,Loo A,Chen L,Lenz P,Waters NJ,Schuler W,Dörken B,Yao YM,Warmuth M,Lenz G,Stegmeier Fdoi
10.1158/0008-5472.CAN-10-2525subject
Has Abstractpub_date
2011-04-01 00:00:00pages
2643-53issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-10-2525journal_volume
71pub_type
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