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Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma.

  • Besse A Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
  • Stolze SC Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
  • Rasche L Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Weinhold N Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Morgan GJ Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • Kraus M Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
  • Bader J Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
  • Overkleeft HS Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, Leiden, The Netherlands.
  • Besse L Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
  • Driessen C Experimental Oncology and Hematology, Department of Oncology and Hematology, Kantonsspital St Gallen, St Gallen, Switzerland.
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  • 2017-07-06
Published in:
  • Leukemia. - 2018
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
Bortezomib
Cell Line, Tumor
Drug Resistance, Neoplasm
HIV Protease Inhibitors
Humans
Lopinavir
Multiple Myeloma
Nelfinavir
Oligopeptides
Plasma Cells
Proteasome Endopeptidase Complex
Proteasome Inhibitors
English Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.
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  • English
Open access status
hybrid
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Persistent URL
https://folia.unifr.ch/global/documents/77100
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