EGFR and Prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer
EGFR and Prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer
复制标题
DOI：
10.1002/1878-0261.12411
复制
发表时间：
2019-04-01
影响因子：
6.6
通讯作者：
Wiegmans, Adrian P.
中科院分区：
文献类型：
--
作者：
Atkinson, Caroline J.;Kawamata, Futoshi;Wiegmans, Adrian P.
表皮生长因子受体(EGFR)通过致癌信号支持结直肠癌的进展。抗EGFR治疗作为结直肠癌的一种临床选择正在研究中，已经在神经细胞中检测到EGFR和Prion蛋白之间的相互作用。我们假设Prpa(C)的表达水平可能调节EGFR信号通路，对该信号通路的详细了解可能有助于确定结直肠癌的耐药机制和新的可操作靶点。我们在通过吉非替尼敲除Prpa(C)或抑制EGFR信号之后进行了分子通路分析，以确定决定细胞对顺铂敏感性或耐药性的关键信号蛋白表达的变化。这些蛋白的表达在配对的原发和转移患者样本中被检测，并与对治疗的抵抗和疾病的进展相关。利用三个结直肠癌细胞系，我们观察到Prpa(C)的高表达与顺铂耐药之间的相关性。对耐药细胞系的分子信号研究表明，Prpa(C)通过与EGFR共定位参与信号传递，而这一作用可以通过靶向p38丝裂原激活蛋白激酶(P38 MAPK)来克服。我们发现，Kruppel样因子5(KLF5)是p38MAPK下游的靶标，它的水平可以预测细胞系和患者对铂类药物的反应。此外，在BRAF突变的结直肠癌中观察到KLF5的高表达。我们的研究表明，EGFR到KLF5的通路可以预测铂类药物治疗的患者进展。
Epidermal growth factor receptor (EGFR) supports colorectal cancer progression via oncogenic signaling. Anti-EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that PrPA (c) expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of PrPA (c) or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of PrPA (c) and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that PrPA (c) contributed to signaling via colocalization with EGFR, which could be overcome by targeting p38 mitogen-activated protein kinases (p38 MAPK). We revealed that the level of Kruppel-like factor 5 (KLF5), a target downstream of p38 MAPK, was predictive for cell line and patient response to platinum agents. Further, high KLF5 expression was observed in BRAF-mutant colorectal cancer. Our study indicates that the EGFR to KLF5 pathway is predictive of patient progression on platinum-based therapy.