| First Author | Park E | Year | 2020 |
| Journal | Sci Transl Med | Volume | 12 |
| Issue | 526 | PubMed ID | 31941829 |
| Mgi Jnum | J:283271 | Mgi Id | MGI:6386046 |
| Doi | 10.1126/scitranslmed.aax9340 | Citation | Park E, et al. (2020) Stromal cell protein kinase C-beta inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci Transl Med 12(526) |
| abstractText | 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)-beta-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-beta 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-beta 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-beta-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-beta, enhance the effectiveness of many antileukemic therapies. |
