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

Carfilzomib resistance due to ABCB1/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma.
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Besse A, Stolze SC, Rasche L, Weinhold N, Morgan GJ, Kraus M, Bader J, Overkleeft HS, Besse L, Driessen C,


Besse A, Stolze SC, Rasche L, Weinhold N, Morgan GJ, Kraus M, Bader J, Overkleeft HS, Besse L, Driessen C, (click to view)

Besse A, Stolze SC, Rasche L, Weinhold N, Morgan GJ, Kraus M, Bader J, Overkleeft HS, Besse L, Driessen C,

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Leukemia 2017 07 05() doi 10.1038/leu.2017.212

Abstract

Proteasome inhibitor carfilzomib has activity superior to bortezomib and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience proteasome inhibitor-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 carfilzomib-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PC) vs untreated patients’ bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of carfilzomib due to drug efflux, in contrast to bortezomib. 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 and lopinavir as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. Nelfinavir and lopinavir restored carfilzomib 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 carfilzomib.Leukemia accepted article preview online, 05 July 2017. doi:10.1038/leu.2017.212.

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