PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

Abstract

Key Points• AEB071 demonstrates preclinical in vitro and in vivo activity against CLL independent of survival signaling and stromal cell protection.• AEB071 can either inhibit or activate the WNT pathway emphasizing the importance of pharmacodynamic monitoring in its development.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-b (PKC-b) 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 b-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-b 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 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted. (Blood. 2014;124(9):1481-1491) IntroductionChronic lymphocytic leukemia (CLL) is one of the most common types of adult leukemia and is currently incurable. Decades of research into the biology of CLL and other B-cell malignancies has brought forth B-cell receptor (BCR) signaling as a common required driving force in the survival and proliferation of these tumor cells. Several survival pathways involved in BCR signaling, including the phosphatidylinositol 3-kinase (PI3K), nuclear factor-kB (NF-kB), and mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK), are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs. [1][2][3] Efforts to target BCR signaling with therapeutic agents which reversibly inhibit PI3K-d 4,5 or irreversibly inhibit Bruton tyrosine kinase (BTK) 6-8 have shown significant clinical activity in CLL, including those with high-risk genomic disease, and are currently in phase 3 studies. Protein kinase C-b (PKC-b) is an immediate downstream target of BTK that has recently been shown to be overexpressed in CLL 9 and is essential to the in vivo development of CLL in Em-TCL1 mice. 10 In B cells, PKC-b is thought to be the predominant PKC isoform mediating BCRdependent NF-kB activation.11-13 Downstream of PKC-b, IkB kinase and caspase recruitment domain-containing protein 11 (CARD11 [also known as CARMA1]) are phosphorylated, le...

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

“…In multiple myeloma, pharmacologic inhibition of activated PKCbII using enzastaurin inhibited growth factors and cytokines secreted by multiple myeloma-derived bone marrow stromal cells (28). In CLL, PKCb is immediately downstream of the B-cell receptor and has been shown to be important to CLL cell autocrine survival and proliferation in vivo (43). PKCb is also essential for the development of CLL in the TCL1 transgenic mouse model, making it a valid therapeutic target in this malignancy (44).…”

Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

“…49 In support of this, AEB071 is currently being studied in a phase II clinical trial in diffuse large B-cell lymphoma, and has recently been demonstrated to have pre-clinical activity in CLL in vitro and in vivo. 50 Targeting PKC, and in particular PKCb, is especially pertinent given the recent findings of Lutzny et al, who demonstrated that PKCbII expression in bone marrow stromal cells is essential for the survival and development of CLL cells. 51 Therefore, inhibition of PKCb may modify the tumor microenvironment, which has been established to play a critical role in supporting CLL survival, proliferation and chemoresistance.…”

How I manage ibrutinib-refractory chronic lymphocytic leukemia

“…For those with PCLG2 mutations or BTK mutations, other downstream targets such as PKCb might also be clinically relevant. Preclinical testing with sotrastaurin has shown proof of concept in this area 35 ; however, clinical studies are not being pursued in this population with this particular agent.…”