Exploration of Proteins Involved in Acquisition of Resistance to Cetuximab
Exploration of Proteins Involved in Acquisition of Resistance to Cetuximab
复制标题
DOI：
10.24198/idjp.v1i1.19582
复制
发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Hironori Nakamura;A. Nagamine;H. Yashima;T. Araki;Koujirou Yamamoto
中科院分区：
文献类型：
--
作者：
Hironori Nakamura;A. Nagamine;H. Yashima;T. Araki;Koujirou Yamamoto
抗表皮生长因子受体（EGFR）单克隆抗体（Mab）在约50%的野生型KRAS结直肠癌（CRC）患者中显示出高疗效。然而，< 20%的KRAS野生型CRC患者对这些药物具有持续的治疗效果，并且获得性耐药已成为严重的临床问题。在本研究中，为了阐明与西妥昔单抗（Cmab）获得耐药相关的因素并制定针对此类获得性耐药的对策，我们通过蛋白质组学方法使用来自CmAb敏感的CRC细胞系和原始细胞系的获得性耐药细胞系进行了全面的蛋白质分析。通过将SW 48和C99细胞系连续暴露于CmAb来产生CmAb获得性抗性细胞系。在C99和SW 48细胞系中，dCK和锌指和含BTB结构域的蛋白41（ZBTB 41）的表达增加超过10倍，双特异性蛋白磷酸酶3（DUS 3）的表达降低不到1/10，从而获得对Cmab的抗性。因为dCK的过表达被认为是核苷类似物如阿糖胞苷或吉西他滨功效的阳性指标，所以认为由dCK激活的核苷类似物可以是治疗具有获得性CmAb抗性的癌症的有用药剂。未来，我们需要阐明这些药物对治疗Cmab耐药的CRC的有用性，并评估通过调节ZBTB 41和DUS 3表达恢复Cmab敏感性的可能性.Keyword：cetuximab，colorectal cancer，acquired resistance，protein，dCK，ZBTB 41
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) show high efficacy in about 50% of colorectal cancer (CRC) patients with wild-type KRAS. However, < 20% of patients with KRAS wild-type CRC have continued therapeutic effects with these agents, and acquired resistance to treatment has become a serious clinical problem. In this study, to clarify the factors related to acquisition of resistance to cetuximab (Cmab) and establish countermeasures against such acquired resistance, we conducted a comprehensive protein analysis via a proteomics approach using acquired resistance cell lines derived from Cmab-sensitive CRC cell lines and original cell lines. Cmab-acquired resistance cell lines were generated by continuous exposure of SW48 and C99 cell lines to Cmab. Expression of dCK and zinc finger and BTB domain-containing protein 41 (ZBTB41) increased more than 10-fold, and dual specificity protein phosphatase 3 (DUS3) expression decreased by less than 1/10 with acquisition of resistance to Cmab in both C99 and SW48 cell lines. Because overexpression of dCK is known as a positive indicator of efficacy of nucleoside analogs such as cytarabine or gemcitabine, it is considered that nucleoside analogs activated by dCK may be useful agents in treatment of cancers with acquired Cmab-resistance. In the future, we need to clarify the usefulness of these drugs for the treatment of Cmab resistant CRC and to assess the possibility of restoration of Cmab sensitivity by regulation of ZBTB41 and DUS3 expression.Keyword : cetuximab, colorectal cancer, acquired resistance, protein, dCK, ZBTB41