title: Protein kinase C inhibitor sotrastaurin selectively inhibits the growth of CD79 mutant diffuse large B-cell lymphomas.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Naylor
authors.forename: Huaping
authors.initials: H
authors.lastname: Tang
authors.forename: Boris A
authors.initials: BA
authors.lastname: Ratsch
authors.forename: Andreas
authors.initials: A
authors.lastname: Enns
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.forename: Liqing
authors.initials: L
authors.lastname: Chen
authors.forename: Peter
authors.initials: P
authors.lastname: Lenz
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
authors.forename: Walter
authors.initials: W
authors.lastname: Schuler
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Yung-Mae
authors.initials: YM
authors.lastname: Yao
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D051925:CD79 Antigens / Q000235:genetics*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016193:G1 Phase / Q000187:drug effects; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051562:Proto-Oncogene Proteins c-bcr / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053468:CARD Signaling Adaptor Proteins; D051925:CD79 Antigens; C497881:CD79A protein, human; C497883:CD79B protein, human; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D011493:Protein Kinase C; C426242:CARD11 protein, human; D006162:Guanylate Cyclase