Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells
Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells
复制标题
结直肠癌细胞中核糖体蛋白S6磷酸化的早期反应与曲美替尼敏感性相关
DOI：
10.1038/s41374-021-00590-w
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发表时间：
2021-04-28
影响因子：
5
通讯作者：
Murakami, Kazunari
中科院分区：
文献类型：
--
作者：
Hirashita, Yuka;Tsukamoto, Yoshiyuki;Murakami, Kazunari
降低的pS 6与结肠直肠癌类器官以及细胞系中对MEK抑制的敏感性相关。本研究通过使用pS 6水平的变化作为预测性诊断标志物，显示MEK抑制剂对RAS/BRAF突变的结直肠癌患者亚组的潜在适用性。RAS或BRAF突变与结直肠癌（CRC）的不良预后和对表皮生长因子受体（EGFR）靶向治疗的耐药性相关。尽管它们具有激活下游基因（如MEK和ERK）的共同能力，但MEK抑制剂对RAS/BRAF突变型CRC患者的治疗益处有限，这突出了对生物标志物的需求，以预测MEK抑制的疗效。先前，我们报道了MEK抑制后核糖体蛋白S6（pS 6）磷酸化的变化与胃癌细胞对MEK抑制的敏感性显著相关。在这里，我们使用患者来源的CRC类器官研究了pS 6中的响应值，用于预测曲美替尼（一种MEK抑制剂）在RAS/BRAF突变型CRC患者中的疗效。我们发现一部分CRC细胞系和类器官对曲美替尼敏感。磷酸化ERK（RAS/RAF/MEK通路的下游分子）的变化与曲美替尼敏感性无显著相关性。另一方面，只有那些敏感的人显示出对曲美替尼的响应的pS 6水平降低。曲美替尼处理后pS 6的变化可通过Western印迹、免疫组织化学或免疫细胞化学检测。我们还使用异种移植模型证明了MEK抑制对体内pS 6的影响。我们的数据表明，结合患者来源的类器官，基于免疫染色的pS 6检测可能有助于预测曲美替尼的敏感性。
Reduced pS6 correlates with sensitivity to MEK inhibition in colorectal cancer organoids as well as cell lines. This study shows the potential applicability of MEK inhibitors for a subset of colorectal cancer patients with RAS/BRAF mutation by using the change in pS6 levels as a predictive diagnostic marker.Mutations in RAS or BRAF are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer (CRC). Despite their common ability to activate downstream genes such as MEK and ERK, the therapeutic benefit of MEK inhibitors for patients with RAS/BRAF mutant CRC is limited, highlighting the need for biomarkers to predict the efficacy of MEK inhibition. Previously, we reported that a change in phosphorylation of ribosomal protein S6 (pS6) after MEK inhibition was significantly associated with sensitivity to MEK inhibition in gastric cancer cells. Here, we investigated the value of the response in pS6 for predicting the efficacy of trametinib, a MEK inhibitor, in patients with RAS/BRAF mutant CRC using patient-derived CRC organoids. We found that a subset of CRC cell lines and organoids were sensitive to trametinib. The change in phosphorylated ERK, a downstream molecule of the RAS/RAF/MEK pathway, was not significantly associated with trametinib sensitivity. On the other hand, only those with sensitivity showed a reduction of pS6 levels in response to trametinib. The change in pS6 after trametinib treatment was detectable by Western blotting, immunohistochemistry or immunocytochemistry. We also demonstrated an impact of MEK inhibition on pS6 in vivo using a xenograft model. Our data suggest that, in combination with patient-derived organoids, immunostaining-based detection of pS6 could be useful for prediction of trametinib sensitivity.