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

• Published in: Science translational medicine 2020-01, Vol.12 (526)
• Main Authors: Park, Eugene, Chen, Jingyu, Moore, Andrew, Mangolini, Maurizio, Santoro, Antonella, Boyd, Joseph R, Schjerven, Hilde, Ecker, Veronika, Buchner, Maike, Williamson, James C, Lehner, Paul J, Gasparoli, Luca, Williams, Owen, Bloehdorn, Johannes, Stilgenbauer, Stephan, Leitges, Michael, Egle, Alexander, Schmidt-Supprian, Marc, Frietze, Seth, Ringshausen, Ingo
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; B-cell lymphoma; Bcl-x protein; Bone marrow; Chemotherapy; Cytotoxicity; Drug resistance; Drug Resistance, Neoplasm - genetics; Extracellular signal-regulated kinase; Humans; Lymphocytes B; Phosphorylation - drug effects; Protein kinase C; Protein Kinase C beta - metabolism; Signal transduction; Signal Transduction - genetics; Signal Transduction - physiology; Stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Transcription activation; Tumor cells; Tumor Cells, Cultured
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.aax9340

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-X ) 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.