IRAK1激酶在结直肠癌中作为西妥昔单抗协同作用靶标的机制研究

Clinical reports with the use of monoclonal anti-bodies directed against the ligand-binding site of the epidermal growth factor receptor (EGFR) have shown promising results in the treatment of colorectal cancer. However, due to the exsitance of primary and development of secondary drug resistance, the efficacy of these agents is uaually indurable. It is now widely accepted that KRAS mutation contributes to Cetuximab resistance in colorectal cancer, but mechanisms that underlie the resistance to Cetuximab in KRAS wild type colorectal cancers is not well characterized. We have previously screened the effect of knocking down a panel of intracellular protein kinases on the responses of colorectal cancer cells to Cetuximab based on a bioinformatics datasheet and a synergistic effect between IRAK1 inhibition and Cetuximab was observed.Considering that IRAK1 dowmstream of TLR4 could activate PI3K/Akt and NF-κB et al, which has been reported to contribute to Cetuximab resistance in colorectal cancers, we hypothesize that Cetuximab administration activates IRAK1, which in turns activates PI3K and NF-κB, resulting in Cetuximab resistance. The current proposal was designed to verify the hypothesis.The study will further our understanding of the mechanisms involved in Cetuximab resistance, help with the development of new targetting agents and regimen.

针对EGFR的靶向治疗为结直肠癌的治疗带来了新的希望，然而由于原发或继发性耐药的存在，其作用效果往往不能持久。目前已知KRAS突变可导致肿瘤细胞对EGFR靶向治疗的耐药，但是对于KRAS野生型结直肠癌细胞耐药的机制尚未完全阐明。前期我们通过对西妥昔处理的体外培养结肠癌组织进行基因芯片分析结合细胞高内涵筛选实验发现IRAK1激酶具有协同克服结肠癌对西妥昔单抗耐药的作用。回顾文献发现，IRAK1激酶可激活下游NF-κB、PI3K/Akt等与结直肠癌细胞对西妥昔单抗的耐药密切相关的信号通路。基于上述发现，我们提出西妥昔处理激活细胞内IRAK1下游信号通路导致肿瘤细胞对西妥昔单抗治疗的耐药，靶向IRAK1可协同西妥昔单抗发挥抗肿瘤作用。本项目将在前期工作基础通过体内外实验验证这一假说。本项目对于揭示KRAS野生型结直肠癌细胞耐EGFR靶向治疗的新机制，开发新的靶向药物和治疗方案具有重要意义。

EGFR 靶向治疗的出现给结直肠癌患者带来了新的希望，但是由于原发或继发性耐药的存在，导致其作用效果往往不能持久。目前已知结肠癌患者对西妥昔单抗耐药的主要原因是 KRAS 基因的突变，然而对于 KRAS 野生型结直肠癌细胞的耐药机制尚未完全阐明。前期研究中我们通过对西妥昔处理的体外培养结肠癌组织进行基因芯片分析和细胞高内涵筛选实验发现 IRAK1 激酶具有协同克服结肠癌对西妥昔单抗耐药的作用。回顾文献发现，IRAK1 激酶可激活下游 NF-κB、PI3K/Akt 等与结直肠癌细胞对西妥昔单抗耐药密切相关的信号通路。因此我们猜想西妥昔单抗激活肿瘤细胞内 IRAK1 介导的信号通路导致对耐药现象的出现，靶向抑制 IRAK1 可协同西妥昔单抗的抗肿瘤作用。本研究将在前期工作基础通过体内外实验来验证这一假说。本项目对于揭示 KRAS 野生型结直肠癌细胞耐 EGFR 靶向治疗的新机制，对于开发新的靶向药物和治疗方案具有重要意义。