TY - JOUR
T1 - PKC-β as a therapeutic target in CLL
T2 - PKC inhibitor AEB071 demonstrates preclinical activity in CLL
AU - El-Gamal, Dalia
AU - Williams, Katie
AU - LaFollette, Taylor D.
AU - Cannon, Matthew
AU - Blachly, James S.
AU - Zhong, Yiming
AU - Woyach, Jennifer A.
AU - Williams, Erich
AU - Awan, Farrukh T.
AU - Jones, Jeffrey
AU - Andritsos, Leslie
AU - Maddocks, Kami
AU - Wu, Chia Hsien
AU - Chen, Ching Shih
AU - Lehman, Amy
AU - Zhang, Xiaoli
AU - Lapalombella, Rosa
AU - Byrd, John C.
PY - 2014/8/28
Y1 - 2014/8/28
N2 - Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 asmonotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
AB - Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 asmonotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907322714&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-05-574830
DO - 10.1182/blood-2014-05-574830
M3 - Article
C2 - 25001469
AN - SCOPUS:84907322714
SN - 0006-4971
VL - 124
SP - 1481
EP - 1491
JO - Blood
JF - Blood
IS - 9
ER -