Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Graduate Program in Bioindustrial Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea; Division of Biohealthcare, Department of Echo-Applied Chemistry, Daejin University, 1007 Hoguk-ro, Pocheon-si, Gyeonggi-do, 11159, Republic of Korea.
Biomaterials. 2023 Dec;303:122382. doi: 10.1016/j.biomaterials.2023.122382. Epub 2023 Nov 3.
Anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, therapy has significantly improved the clinical outcomes of patients with colorectal cancer, but the response to cetuximab can vary widely among individuals. We thus need strategies for predicting the response to this therapy. However, the current methods are unsatisfactory in their predictive power. Cetuximab can promote the internalization and degradation of EGFR, and its therapeutic efficacy is significantly correlated with the degree of EGFR degradation. Here, we present a new approach to predict the response to anti-EGFR therapy, cetuximab by evaluating the degree of EGFR internalization and degradation of colorectal cancer cells in vitro and in vivo. Our newly developed fluorogenic cetuximab-conjugated probe (Cetux-probe) was confirmed to undergo EGFR binding, internalization, and lysosomal degradation to yield fluorescence activation; it thus shares the action mechanism by which cetuximab exerts its anti-tumor effects. Cetux-probe-activated fluorescence could be used to gauge EGFR degradation and showed a strong linear correlation with the cytotoxicity of cetuximab in colorectal cancer cells and tumor-bearing mice. The predictive ability of Cetux-probe-activated fluorescence was much higher than those of EGFR expression or KRAS mutation status. The Cetux-probes may become useful tools for predicting the response to cetuximab therapy by assessing EGFR degradation.
抗表皮生长因子受体 (EGFR) 抗体，西妥昔单抗，治疗显著改善了结直肠癌患者的临床结局，但西妥昔单抗的反应在个体之间差异很大。因此，我们需要预测这种治疗反应的策略。然而，目前的方法在预测能力方面并不令人满意。西妥昔单抗可以促进 EGFR 的内化和降解，其治疗效果与 EGFR 降解的程度显著相关。在这里，我们提出了一种新的方法来预测抗 EGFR 治疗，西妥昔单抗通过评估结直肠癌细胞在体外和体内的 EGFR 内化和降解程度。我们新开发的荧光西妥昔单抗缀合探针（Cetux-probe）被证实能够与 EGFR 结合、内化和溶酶体降解以产生荧光激活；因此，它与西妥昔单抗发挥抗肿瘤作用的作用机制相同。Cetux-probe 激活的荧光可用于衡量 EGFR 降解，并与西妥昔单抗在结直肠癌细胞和荷瘤小鼠中的细胞毒性呈强线性相关。Cetux-probe 激活荧光的预测能力明显高于 EGFR 表达或 KRAS 突变状态。Cetux-probes 可能成为通过评估 EGFR 降解来预测西妥昔单抗治疗反应的有用工具。
