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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DOI：
10.1038/leu.2017.212
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Driessen C
中科院分区：
文献类型：
--
作者：
Besse A;Stolze SC;Rasche L;Weinhold N;Morgan GJ;Kraus M;Bader J;Overkleeft HS;Besse L;Driessen C
蛋白酶体抑制剂（PI）卡非佐米（CFZ）的活性上级于硼替佐米（BTZ），越来越多地用于多发性骨髓瘤（MM）的一线治疗和复发情况。大多数MM患者最终会发生PI难治性疾病，这是一种未满足的医疗需求，生物学了解不多，结局令人沮丧。ABCB 1的药理学靶向改善了患者的结局，包括MM，但遭受了药物不良反应和血药浓度不足。蛋白质组学分析确定ABCB 1过表达是CFZ耐药MM细胞中最显著的变化。我们研究了ABCB 1过表达在MM中的功能作用，并观察到ABCB 1在外周血恶性浆细胞（PC）中与未经治疗的患者骨髓PC相比显著上调。与BTZ相比，ABCB 1过表达降低了CFZ由于药物外排引起的蛋白酶体抑制活性。同样，在表达ABCB 1的MM细胞中，已建立的抗MM药物的细胞毒性显著降低。在临床试验中寻找靶向ABCB 1的潜在药物时，我们确定了HIV蛋白酶抑制剂奈非那韦（NFV）和洛匹那韦（LPV）作为ABCB 1介导的药物输出的有效功能调节剂，最有可能通过调节线粒体通透性转换孔。NFV和LPV在治疗相关的药物水平恢复了CFZ活性，因此代表了在临床试验中测试的即用型药物，以靶向ABCB 1并使PC对已建立的骨髓瘤药物，特别是CFZ重新敏感。
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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影响因子：
11.4
作者：
Kumar SK;Lee JH;Lahuerta JJ;Morgan G;Richardson PG;Crowley J;Haessler J;Feather J;Hoering A;Moreau P;LeLeu X;Hulin C;Klein SK;Sonneveld P;Siegel D;Bladé J;Goldschmidt H;Jagannath S;Miguel JS;Orlowski R;Palumbo A;Sezer O;Rajkumar SV;Durie BG;International Myeloma Working Group
通讯作者：
International Myeloma Working Group
影响因子：
120.1
作者：
Flexner, Charles
通讯作者：
Flexner, Charles
影响因子：
10.1
作者：
Driessen, Christoph;Kraus, Marianne;Mey, Ulrich J. M.
通讯作者：
Mey, Ulrich J. M.
影响因子：
11.5
作者：
Hill, Esme J.;Roberts, Corran;Sharma, Ricky A.
通讯作者：
Sharma, Ricky A.
影响因子：
2
作者：
Kageyama, M;Namiki, H;Takada, K
通讯作者：
Takada, K