MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.
MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.
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DOI：
10.1038/s41598-017-02713-0
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发表时间：
2017-06-02
影响因子：
4.6
通讯作者：
Hazlehurst LA
中科院分区：
文献类型：
--
作者：
Emmons MF;Anreddy N;Cuevas J;Steinberger K;Yang S;McLaughlin M;Silva A;Hazlehurst LA
耐药性的出现仍然是改善多发性骨髓瘤治疗结果的主要障碍。MTI-101是一种一流的模拟多肽药物，它与含有CD44/ITGA4的复合体结合，并在多发性骨髓瘤细胞系中触发坏死细胞死亡。在这份报告中，我们证明了对MTI-101的抗性的获得与预测减弱钙离子流量的基因表达的变化相关。与获得性耐药基因一致，MTI-101处理诱导亲本细胞内钙水平快速而强劲地增加；这一发现在获得性耐药细胞系中有所减弱。从机制上讲，我们证明了药物抑制商店操作的通道或减少商店操作的钙通道的一个成分的表达，TRPC1阻断了MTI-101诱导的细胞死亡。重要的是，MTI-101在复发性骨髓瘤患者的标本中更有效，这表明复发可能是以增加对钙超载介导的细胞死亡的敏感性为代价的。最后，我们使用骨髓瘤细胞株和原发骨髓瘤患者标本证明了MTI-101与Bortezomib联合使用时具有协同作用。总之，这些数据继续支持这类用于治疗复发性骨髓瘤的新型化合物的开发。
The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca2+ flux. Consistent with the acquired resistant genotype, MTI-101 treatment induces a rapid and robust increase in intracellular Ca2+ levels in the parental cells; a finding that was attenuated in the acquired drug resistant cell line. Mechanistically, we show that pharmacological inhibition of store operated channels or reduction in the expression of a component of the store operated Ca2+ channel, TRPC1 blocks MTI-101 induced cell death. Importantly, MTI-101 is more potent in specimens obtained from relapsed myeloma patients, suggesting that relapse may occur at a cost for increased sensitivity to Ca2+ overload mediated cell death. Finally, we demonstrate that MTI-101 is synergistic when combined with bortezomib, using both myeloma cell lines and primary myeloma patient specimens. Together, these data continue to support the development of this novel class of compounds for the treatment of relapsed myeloma.