Thymidine Kinase 1 Loss Confers Trifluridine Resistance without Affecting 5-Fluorouracil Metabolism and Cytotoxicity
Thymidine Kinase 1 Loss Confers Trifluridine Resistance without Affecting 5-Fluorouracil Metabolism and Cytotoxicity
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DOI：
10.1158/1541-7786.mcr-17-0686
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发表时间：
2018-10-01
影响因子：
5.2
通讯作者：
Maehara, Yoshihiko
中科院分区：
文献类型：
--
作者：
Edahiro, Keitaro;Iimori, Makoto;Maehara, Yoshihiko
对治疗药物的获得性耐药性是接受系统治疗的癌症患者的严重问题。在实验上，通过反复、连续暴露于浓度递增的药物，在体外细胞系中建立耐药性;然而，获得性耐药性的确切机制并不总是已知的。在此，证明了对曲氟尿苷（FTD）（新型口服核苷类似物型化疗药物曲氟尿苷/替吡嘧啶的关键组分）具有获得性耐药的人结直肠癌细胞系DLD 1由于编码外显子中的一个无义突变而缺乏功能性胸苷激酶1（TK 1）表达。TK 1基因的靶向破坏也赋予了重度FTD耐药性，表明TK 1蛋白表达的缺失是FTD耐药性的主要原因。FTD耐药的DLD 1细胞和DLD 1-TK 1（-/-）细胞均表现出与亲本DLD 1系相似的5-氟尿嘧啶（5-FU）敏感性。这些细胞中细胞嘧啶核苷酸的数量和5-FU处理细胞中胸苷酸合成酶三元复合物形成的动力学与DLD 1细胞相似，表明5-FU代谢和细胞毒性不受影响。当前数据提供了基于分子的证据，证明获得性FTD耐药不会导致5-FU耐药，这意味着即使在曲氟尿苷/替吡嘧啶治疗期间FTD难治性肿瘤中，基于5-FU的化疗也有效。(C)2018年AACR。
Acquired resistance to therapeutic drugs is a serious problem for patients with cancer receiving systemic treatment. Experimentally, drug resistance is established in cell lines in vitro by repeated, continuous exposure to escalating concentrations of the drug; however, the precise mechanism underlying the acquired resistance is not always known. Here, it is demonstrated that the human colorectal cancer cell line DLD1 with acquired resistance to trifluridine (FTD), a key component of the novel, orally administered nucleoside analoguetype chemotherapeutic drug trifluridine/tipiracil, lacks functional thymidine kinase 1 (TK1) expression because of one nonsense mutation in the coding exon. Targeted disruption of the TK1 gene also conferred severe FTD resistance, indicating that the loss of TK1 protein expression is the primary cause of FTD resistance. Both FTD-resistant DLD1 cells and DLD1-TK1(-/-) cells exhibited similar 5-fluorouracil (5-FU) sensitivity to that of the parental DLD1 line. The quantity of cellular pyrimidine nucleotides in these cells and the kinetics of thymidylate synthase ternary complex formation in 5-FU-treated cells is similar to DLD1 cells, indicating that 5-FU metabolism and cytotoxicity were unaffected. The current data provide molecular-based evidence that acquired resistance to FTD does not confer 5-FU resistance, implying that 5-FU-based chemotherapy would be effective even in tumors that become refractory to FTD during trifluridine/tipiracil treatment. (C) 2018 AACR.