Research ArticleCancer

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

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Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaax9340
DOI: 10.1126/scitranslmed.aax9340

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Just as the tumor microenvironment influences the behavior of solid tumors, hematological malignancies are affected by the microenvironment in the bone marrow stroma. Park et al. identified a pathway dependent on protein kinase C-β from the stromal cells, which promotes survival and drug resistance in B cell malignancies. The authors examined the mechanism for the observed effects and then identified small-molecule compounds for potential intervention. Inhibiting the protein kinase C-β signaling pathway in stromal cells sensitized these cancers to a variety of drugs and extended survival in both genetic and patient-derived mouse models of cancer.

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.

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