The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer
The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer
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ERK抑制剂敏感性与结直肠癌分子特征之间的关联
DOI：
10.1016/j.bbrc.2021.04.130
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发表时间：
2021
影响因子：
3.1
通讯作者：
Furukawa Toru
中科院分区：
文献类型：
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作者：
Tayama Hodaka;Karasawa Hideaki;Yamamura Akihiro;Okamura Yasunobu;Katsuoka Fumiki;Suzuki Hideyuki;Kajiwara Taiki;Kobayashi Minoru;Hatsuzawa Yuuri;Shiihara Masahiro;Bin Li;Gazi Md Yeashin;Sato Mizuki;Kumada Kazuki;Ito Shigehiro;Shimada Muneaki;Furukawa Toru
丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路在结直肠癌的发生发展中起重要作用，被认为是由BRAF或KRAS等基因突变激活的。尽管细胞外信号调节激酶（ERK）抑制剂已在BRAF或KRAS突变的细胞中表现出疗效，但临床反应并不总是与分子特征相关。病人源性类器官（PDO）是研究肿瘤的一种有效的体外模型系统，在药物筛选中得到了广泛的应用。本研究旨在分析通过下一代测序（NGS）分析的分子特征与对ERK抑制剂（即，SCH 772984）。使用14个CRC细胞系进行了SCH 772984的药物敏感性试验，结果表明敏感性与BRAF突变一致，但与KRAS状态不完全一致。在PDO的药物敏感性试验中，7例BRAF或KRAS突变病例中有6例显示对SCH 772984敏感，而6例BRAF和KRAS野生型病例中有5例耐药。本研究的结果表明，临床标本的分子状态可能代表PDO的敏感性，但不一定绝对重叠。PDO可能能够弥补基因组的局限性，并有可能提供一种新的精确医学。
The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerfulin vitromodel system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.