Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors.
Distinct Response of Circulating microRNAs to the Treatment of Pancreatic Cancer Xenografts with FGFR and ALK Kinase Inhibitors.
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DOI：
10.3390/cancers14061517
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发表时间：
2022-03-16
期刊：
影响因子：
5.2
通讯作者：
Wellstein A
中科院分区：
文献类型：
--
作者：
Peran I;Vietsch EE;Yan G;Riegel AT;Wellstein A
胰腺癌是美国癌症相关死亡的三大主要原因之一，主要是由于疾病已经扩散到其他器官后的晚期诊断。因此，及时和有效的治疗是必要的，以改善结果。在这项研究中，我们探索了使用从胰腺癌荷瘤小鼠外周血中收集的循环microRNA（miR）来评估治疗方案早期的治疗效果。在治疗期间，血清样品中的microRNA变化先于组织学变化，这表明循环microRNA可用作治疗反应的早期指标。这些易于获得的生物标志物可以重复采样，并可以指导及时的治疗决策。胰腺癌通常在晚期检测到，因此对治疗的敏感性有限，使其成为最致命的恶性肿瘤之一。在这项研究中，我们评估了外周血中微小RNA（miR）模式的变化，作为胰腺癌对靶向肿瘤-间质相互作用的抑制剂的治疗反应的潜在读数。用成纤维细胞生长因子受体激酶（FGFR; PD 173074）或间变性淋巴瘤激酶受体（ALK; TAE 684）抑制剂处理胰腺癌细胞（COLO 357 PL）异种移植物小鼠。虽然两种治疗在相似程度上抑制肿瘤血管生成、信号转导和有丝分裂，但它们导致循环miR特征的明显变化。肿瘤中的miR模式与循环中的miR模式的比较表明，抑制剂可以通过其对肿瘤来源的miR以及宿主来源的循环miR的不同影响来区分。包括循环miR-1和miR-22在内的不同特征分别与ALK和FGFR抑制的疗效相关。我们建议，监测循环miR谱的变化可以提供对通路靶向药物的治疗反应或耐药性的早期特征，从而提供快速评估候选疗法疗效的非侵入性测量。
Pancreatic cancer is among the top three leading causes of cancer-related death in the United States, mainly due to late diagnosis after the disease has already spread to other organs. Hence, timely and efficient treatments are necessary to improve outcomes. In this study, we explored the use of circulating microRNAs (miRs) collected from the peripheral blood of pancreatic cancer-bearing mice for assessment of treatment efficacy early in the treatment schedule. MicroRNA changes in serum samples precede histologic changes during the treatments, suggesting the use of circulating microRNA as early indicators of response to treatment. These easily-accessible biomarkers can be sampled repeatedly and could guide timely treatment decisions. Pancreatic adenocarcinoma is typically detected at a late stage and thus shows only limited sensitivity to treatment, making it one of the deadliest malignancies. In this study, we evaluate changes in microRNA (miR) patterns in peripheral blood as a potential readout of treatment responses of pancreatic cancer to inhibitors that target tumor–stroma interactions. Mice with pancreatic cancer cell (COLO357PL) xenografts were treated with inhibitors of either fibroblast growth factor receptor kinase (FGFR; PD173074) or anaplastic lymphoma kinase receptor (ALK; TAE684). While both treatments inhibited tumor angiogenesis, signal transduction, and mitogenesis to a similar extent, they resulted in distinct changes in circulating miR signatures. Comparison of the miR pattern in the tumor versus that in circulation showed that the inhibitors can be distinguished by their differential impact on tumor-derived miRs as well as host-derived circulating miRs. Distinct signatures that include circulating miR-1 and miR-22 are associated with the efficacy of ALK and FGFR inhibition, respectively. We propose that monitoring changes in circulating miR profiles can provide an early signature of treatment response or resistance to pathway-targeted drugs, and thus provide a non-invasive measurement to rapidly assess the efficacy of candidate therapies.
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