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

Sci Transl Med. 2020 Jan 15;12(526):eaax9340. 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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Phosphorylation / drug effects
  • Protein Kinase C beta / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Tumor Cells, Cultured


  • Protein Kinase C beta