Vorinostat Downregulates CD30 and Decreases Brentuximab Vedotin Efficacy in Human Lymphocytes
Vorinostat Downregulates CD30 and Decreases Brentuximab Vedotin Efficacy in Human Lymphocytes
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DOI：
10.1158/1535-7163.mct-14-0593
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发表时间：
2014-12-01
影响因子：
5.7
通讯作者：
Sample, Clare E.
中科院分区：
文献类型：
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作者：
Hasanali, Zainul S.;Epner, Elliot M.;Sample, Clare E.
随着越来越多的临床试验着眼于癌症的联合疗法，潜在的药物-药物相互作用需要特别关注。一个这样的例子是用抗CD30抗体-药物结合物布妥昔单抗维多丁治疗CD30(+)肿瘤。使用体外培养的B、T和自然杀伤(NK)细胞株，我们证明了SAHA下调CD30的表达，如果基线CD30水平降低50%或更多，则降低随后的布妥昔单抗治疗的疗效。有趣的是，保持50%或更多CD30基础表达的低剂量SAHA治疗，随后使用布妥昔单抗维多丁治疗，导致了增强的抗肿瘤活性。在去除SAHA后，CD30的下调是短暂的，这表明允许SAHA被清除可能会绕过与后续药物治疗的任何相互作用。我们的研究结果证实了CD30对布妥昔单抗疗效的要求，并提示联合SAHA治疗CD30 Dim肿瘤可能会降低疗效。然而，对于高CD30(+)的肿瘤，联合治疗可以提高疗效，值得进一步考虑作为一种新的治疗范式。
With an increasing number of clinical trials looking at combination therapies in cancer, potential drug-drug interactions require particular attention. One such instance is the treatment of CD30(+) tumors after previous vorinostat (SAHA; suberoylanilide hydroxyamic acid) failure with the anti-CD30 antibody-drug conjugate brentuximab vedotin. Using B-, T-, and natural killer (NK)-cell lines in vitro, we demonstrate that SAHA downregulates the expression of CD30 and lowers the efficacy of subsequent brentuximab vedotin treatment if baseline CD30 levels are reduced by 50% or more. Interestingly, low-dose SAHA treatment that maintained 50% or more of basal CD30 expression followed by subsequent treatment with brentuximab vedotin led to enhanced antitumor activity. The downregulation of CD30 was short lived upon SAHA removal, suggesting that allowing SAHA washout may circumvent any interactions with subsequent drug therapies. Our findings confirm the requirement of CD30 for brentuximab vedotin efficacy and suggest that combination treatment with SAHA in CD30 dim tumors may decrease efficacy. Combination treatment in highly CD30(+) tumors, however, increases efficacy and warrants further consideration as a new treatment paradigm.