MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer
MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer
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DOI：
10.1002/ijc.30082
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发表时间：
2016-08-15
影响因子：
6.4
通讯作者：
Domingos Chinen, Ludmilla Thome
中科院分区：
文献类型：
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作者：
Abdallah, Emne Ali;Fanelli, Marcello Ferretti;Domingos Chinen, Ludmilla Thome
循环肿瘤细胞是肿瘤进展的重要标志物，可以反映转移性结直肠癌（mCRC）的肿瘤行为。鉴定赋予治疗抗性的蛋白质是预测患者反应和更好地选择治疗的重要步骤。多药耐药相关蛋白1（MRP 1）和多药耐药相关蛋白4（MRP 4）在伊立替康耐药中起作用，切除修复交叉互补组1（ERCC 1）表达可赋予铂类化合物耐药。我们纳入了34例mCRC患者，其中大多数接受FOLFIRI或FOLFOX化疗（91.1%）。通过ISET（R）技术分离CTC，并在30名患者（88.2%）中鉴定，中值为2.0 CTC/mL（0-31.0）。我们分析了MRP 1、MRP 4和ERCC 1的免疫细胞化学表达，仅在先前可检测到CTC的患者中，根据接受的治疗（分别为n = 19、15和13例患者）。在接受基于伊立替康的化疗的患者中，与MRP 1阴性CTC患者相比，19例MRP 1阳性CTC患者中的4例显示出更差的无进展生存期（PFS）（2.1个月vs. 9.1个月; p = 0.003）。CTC中研究的其他蛋白质均与PFS无显著相关性。我们还通过免疫组化分析了原发肿瘤和转移瘤的组织学切片，发现与临床病理特征或PFS无关。我们的研究结果表明，当在mCRC患者的CTC中发现MRP 1时，MRP 1是对伊立替康治疗耐药的潜在生物标志物。这是一项小型的原理验证研究，这些早期发现需要在更大的患者队列中进行验证。
Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET (R) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients.