Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance.
Science translational medicine
American Association for the Advancement of Science
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Park, E., Chen, J., Moore, A., Mangolini, M., Santoro, A., Boyd, J. R., Schjerven, H., et al. (2020). Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance.. Science translational medicine, 12 (526)https://doi.org/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 stroma 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 stroma cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small molecule PKC-β inhibitors antagonize pro-survival signals from stroma cells and sensitize tumor cells to targeted and non-targeted chemotherapy, leading to enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion- and matrix proteins, required for Phosphoinositide 3-kinases (PI3K) activation and the ERK-mediated stabilization of BCL-XL in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β dependent activation of transcription factor EB (TFEB), regulating lysosome biogenesis and plasma membrane integrity. Stroma directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many anti-leukemic therapies.
This work was funded by Cancer Research UK (CRUK; C49940/A17480). I.R. is a senior CRUK fellow. M.S.S is supported by the DFG through SCHM2440/7-1 and CRC1243 (A12). L.G. & O.W. received funding from CWCUK (grant 14-169) and GOSHCC (grant V2617). A.E. receives research grants from the Austrian Science Fund (FWF; Transcan I2795-B28 to A.E. (FIRE-CLL), DACH grants I3282-B26 and I1299-B21 (FOR2036) and a grant from the Paracelsus Medical University (PMU Grant E-13/18/091-EGF). S.S. receives funding from the DFG (SFB1074 , project B1), relevant to this work.
Cancer Research UK (17480)
Wellcome Trust (210688/Z/18/Z)
External DOI: https://doi.org/10.1126/scitranslmed.aax9340
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300977