Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas
In: Cancer research (Chicago, Ill.), Jg. 71 (2011), Heft 7, S. 2643-2653
Online
academicJournal
- print, 39 ref
Zugriff:
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 CARD 11 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.
Titel: |
Protein Kinase C Inhibitor Sotrastaurin Selectively Inhibits the Growth of CD79 Mutant Diffuse Large B-Cell Lymphomas
|
---|---|
Autor/in / Beteiligte Person: | NAYLOR, Tara L ; HUAPING, TANG ; YAO, Yung-Mae ; WARMUTH, Markus ; LENZ, Georg ; STEGMEIER, Frank ; RATSCH, Boris A ; ENNS, Andreas ; LOO, Alice ; LIQING, CHEN ; LENZ, Peter ; WATERS, Nigel J ; SCHULER, Walter ; DÖRKEN, Bernd |
Link: | |
Zeitschrift: | Cancer research (Chicago, Ill.), Jg. 71 (2011), Heft 7, S. 2643-2653 |
Veröffentlichung: | Philadelphia, PA: American Association for Cancer Research, 2011 |
Medientyp: | academicJournal |
Umfang: | print, 39 ref |
ISSN: | 0008-5472 (print) |
Schlagwort: |
|
Sonstiges: |
|