Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance

Abstract

Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell–autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)–β–dependent signals from bone marrow–derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal–regulated kinase (ERK)–mediated stabilization of B cell lymphoma–extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β–dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.

Importance of Crosstalk Between Chronic Lymphocytic Leukemia Cells and the Stromal Microenvironment: Direct Contact, Soluble Factors, and Extracellular Vesicles

“…Idelalisib or duvelisib also reduced the ability of stromal cells to support CLL migration and adhesion (161); (d) finally, targeting the over-expression of BCL2 partially induced by the microenvironment has also been proposed (163,164). adhesion and matrix proteins, required for activation of PI3Ks and ERK-mediated stabilization of BCL-XL in tumor cells (162). Microenvironment stimuli provided during CLL/MSC coculture lead to the increase of BCL2 through Notch-1, Notch-2, Notch-4 signaling (97).…”

“…Complementarily, idelalisib or duvelisib also significantly reduced the ability of stromal cells to support CLL migration and adhesion ( 161 ). Another way to disrupt CLL/MSC crosstalk and overcoming drug resistance in CLL patients is to directly target PKC-β signaling pathway in MSC: indeed, Park et al showed that small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and non-targeted chemotherapy, resulting in enhanced cytotoxicity ( 162 ). In addition, they also showed that stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of PI3Ks and ERK-mediated stabilization of BCL-XL in tumor cells ( 162 ).…”

“…Another way to disrupt CLL/MSC crosstalk and overcoming drug resistance in CLL patients is to directly target PKC-β signaling pathway in MSC: indeed, Park et al showed that small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and non-targeted chemotherapy, resulting in enhanced cytotoxicity ( 162 ). In addition, they also showed that stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of PI3Ks and ERK-mediated stabilization of BCL-XL in tumor cells ( 162 ). Microenvironment stimuli provided during CLL/MSC coculture lead to the increase of BCL2 through Notch-1, Notch-2, Notch-4 signaling ( 97 ).…”

Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia

“…Recent studies demonstrates the importance of PKCβ expression in the stromal compartment to protect malignant Bcells from cytotoxic therapies in vivo enrolling a PKCβ-dependent effect in environment-mediated drug resistance of CLL cells. 47,48 Therefore, induced expression of PKCβ may be a common mechanism of malignant cells to harness stromal cells for tumorpromoting purposes. Here, we show that the expression of stromal PKCβ results in metabolic changes and altered ROS production in BMSC.…”

Immune modulatory effects of Idelalisib in stromal cells of chronic lymphocytic leukemia

“…Moreover, the resistance of CLL cells toward drug-induced apoptosis is also mediated by stromal contact, clinically recognized as a minimal-residual disease (MRD) [5]. Recently, in vivo experiments demonstrated that the inhibition of PKCb in stromal cells enhances chemosensitivity in CLL and overcomes drug resistance [6]. It could be shown that stromal contact activates Notch signaling [7] indicating that Notch might play a distinct role in the communication between CLL cells and the microenvironment.…”