Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth
Calcium Release-Activated Calcium (CRAC) Channel Inhibition Suppresses Pancreatic Ductal Adenocarcinoma Cell Proliferation and Patient-Derived Tumor Growth
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DOI：
10.3390/cancers12030750
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发表时间：
2020-03-01
期刊：
影响因子：
5.2
通讯作者：
Azmi, Asfar S.
中科院分区：
文献类型：
--
作者：
Khan, Husain Yar;Mpilla, Gabriel B.;Azmi, Asfar S.
胰腺导管腺癌（PDAC）仍然是一个未解决的临床问题，迫切需要更新的分子驱动治疗方式。已知钙信号，特别是与钙释放激活钙 (CRAC) 通道相关的信号，会影响许多癌症的发生、生长和转移。这是第一项研究 CRAC 通道抑制对 PDAC 细胞系和患者来源的肿瘤模型的影响。在存在或不存在吉西他滨和白蛋白结合型紫杉醇等标准治疗药物的情况下，将 PDAC 细胞系暴露于新型 CRAC 通道抑制剂 RP4010。在存在或不存在化疗药物的情况下，在透明质酸阳性 PDAC 患者来源的异种移植物 (PDx) 中评估 RP4010 的体内功效。用单药 RP4010 治疗 PDAC 细胞系会降低细胞生长，而与吉西他滨/白蛋白结合型紫杉醇的组合在某些剂量组合下表现出协同作用。分子分析表明 RP4010 调节与 CRAC 通道信号通路相关的标记物水平。此外，观察到联合治疗增强了 RP4010 对 CRAC 信号转导分子标志物的影响。在 PDAC PDx 模型中，吉西他滨/白蛋白结合型紫杉醇的存在增强了 RP4010 的抗肿瘤活性。我们的研究表明，针对 CRAC 通道可能是 PDAC 的一种可行的治疗选择，值得进一步的临床评估。
Pancreatic ductal adenocarcinoma (PDAC) remains an unmet clinical problem in urgent need of newer molecularly driven treatment modalities. Calcium signals, particularly those associated with calcium release-activated calcium (CRAC) channels, are known to influence the development, growth, and metastasis of many cancers. This is the first study investigating the impact of CRAC channel inhibition on PDAC cell lines and patient-derived tumor models. PDAC cell lines were exposed to a novel CRAC channel inhibitor, RP4010, in the presence or absence of standard of care drugs such as gemcitabine and nab-paclitaxel. The in vivo efficacy of RP4010 was evaluated in a hyaluronan-positive PDAC patient-derived xenograft (PDx) in the presence or absence of chemotherapeutic agents. Treatment of PDAC cell lines with single-agent RP4010 decreased cell growth, while the combination with gemcitabine/nab-paclitaxel exhibited synergy at certain dose combinations. Molecular analysis showed that RP4010 modulated the levels of markers associated with CRAC channel signaling pathways. Further, the combination treatment was observed to accentuate the effect of RP4010 on molecular markers of CRAC signaling. Anti-tumor activity of RP4010 was enhanced in the presence of gemcitabine/nab-paclitaxel in a PDAC PDx model. Our study indicates that targeting CRAC channel could be a viable therapeutic option in PDAC that warrants further clinical evaluation.