CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin.
CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin.
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DOI：
10.1158/1535-7163.mct-15-0036
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发表时间：
2015-06
影响因子：
5.7
通讯作者：
Kane SE
中科院分区：
文献类型：
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作者：
Chen R;Hou J;Newman E;Kim Y;Donohue C;Liu X;Thomas SH;Forman SJ;Kane SE
Brentuximab vedotin （BV）是一种抗体-药物偶联物，可特异性地向cd30阳性细胞递送强效细胞毒性药物MMAE。BV被fda批准用于治疗复发/难治性霍奇金淋巴瘤（HL）和间变性大细胞淋巴瘤（ALCL）；然而，许多患者没有达到完全缓解，并发展成BV耐药疾病。我们选择了BV抗性HL （L428）和ALCL （Karpas-299）细胞系，使用恒定（ALCL）或脉冲（HL）暴露于BV。我们通过MTS法确认耐药，并通过流式细胞术、qRT-PCR和Western blotting分析耐药细胞中CD30的表达。我们还测量了bv耐药细胞中药物出口蛋白表达、MMAE耐药性和细胞内MMAE浓度。此外，通过免疫组织细胞化学分析10例HL和5例ALCL患者在BV治疗后复发或进展的组织活检样本，检测CD30的表达。与亲代细胞系相比，耐药ALCL细胞系CD30表达下调，而非HL细胞系。相比之下，HL细胞系，而非ALCL细胞系，与亲本系相比，表现出MMAE抗性和MDR1药物出口蛋白的表达增加。对于HL和ALCL，来自BV复发/耐药患者的样本通过免疫组织细胞化学持续表达CD30。1例HL患者通过免疫组织细胞化学表达MDR1。尽管在ALCL体外模型中，CD30表达缺失可能是BV耐药的一种模式，但这一点尚未在患者中得到证实。MMAE耐药和MDR1表达可能是体外和患者对HL的BV耐药模式。
Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically delivers the potent cytotoxic drug MMAE to CD30-positive cells. BV is FDA-approved for treatment of relapsed/refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV resistant disease. We selected for BV-resistant HL (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (HL) exposure to BV. We confirmed drug resistance by MTS assay, and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. Additionally, tissue biopsy samples from 10 HL and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the HL cell line, demonstrated downregulated CD30 expression compared to the parental cell line. In contrast, the HL cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared to the parental line. For both HL and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One HL patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for HL both in vitro and in patients.