Abstract 1630: The PKC inhibitor Sotrastaurin selectively inhibits the growth of CD79 mutant diffuse-large B-cell lymphoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.1630-1630
• Main Authors: Naylor, Tara, Enns, Andreas, Warmuth, Markus, Lenz, Georg, Stegmeier, Frank P.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-1630

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the oncogenic NF-κB pathway and is associated with poor prognosis. Recent studies demonstrated dependence on NF-κB pathway activation and identified genetic lesions in NF-κB pathway regulators, including CARD11/CARMA1, A20/TNFAIP3, and CD79A/B. In this study, we evaluated the therapeutic potential of the selective PKC inhibitor sotrastaurin (STN) in preclinical models of DLBCL. We found that a significant fraction of ABC DLBCL cell lines exhibited strong sensitivity to sotrastaurin and detected that responsiveness can be predicted based on the molecular nature of NF-κB pathway lesions. While mutations in CD79A/B correlate with sensitivity to PKC inhibitors, mutations in CARD11 render ABC DLBCL cell lines insensitive to PKC inhibitors. The growth inhibitory effect of PKC inhibitors correlates with NF-κB pathway inhibition and is mediated by the induction of a G1 cell cycle arrest and/or apoptosis. Collectively, our study provides a strong rationale for the clinical evaluation of sotrastaurin in ABC DLBCL patients that harbor CD79 mutations, and furthermore illustrates the necessity to stratify DLBCL patients according to their genetic abnormalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1630. doi:10.1158/1538-7445.AM2011-1630