Longitudinal plasma proteome profiling reveals the dynamic biomarkers for prediction of cetuximab therapy response in colorectal cancer patients

Cetuximab therapy is the major treatment for colorectal cancer (CRC), but drug resistance limits its effectiveness. Here, we perform longitudinal and deep proteomic profiling of 641 plasma samples originated from 147 CRC patients (CRCs) undergoing cetuximab therapy with multi-course treatment, and 90 healthy controls (HCs). COL12A1, THBS2, S100A8, and S100A9 are screened as potential proteins to distinguish CRCs from HCs both in plasma and tissue validation cohorts. We identify the potential molecular features and biomarkers (RRAS2, MMP8, FBLN1, RPTOR, and IMPDH2) for the initial response prediction. In a longitudinal setting, we identify two clusters with distinct fluctuations and constructed the predictive model with high accuracy to predict the longitudinal response in the multi-course cetuximab treatment, which is further validated in the independent cohort. This study reveals the heterogeneity of different potential biomarkers for tumor diagnosis, the initial response prediction and longitudinal response prediction respectively in the first course and multi-course cetuximab treatment, may ultimately be useful in monitoring and intervention strategies in the management of CRC.

西妥昔单抗（Cetuximab）疗法是结直肠癌（colorectal cancer, CRC）的主流治疗方案，但药物耐药性限制了其临床疗效。本研究针对147例接受多疗程西妥昔单抗治疗的结直肠癌患者的641份血浆样本，以及90例健康对照（healthy controls, HCs），开展了纵向深度蛋白质组学分析。研究筛选出COL12A1、THBS2、S100A8及S100A9作为潜在蛋白标志物，可在血浆与组织验证队列中区分结直肠癌患者与健康对照；同时鉴定出可用于初始治疗应答预测的潜在分子特征与生物标志物（RRAS2、MMP8、FBLN1、RPTOR及IMPDH2）。在纵向研究框架下，本研究鉴定出两个具有显著表达波动特征的蛋白簇，并构建了高精度预测模型，用于预测多疗程西妥昔单抗治疗中的纵向应答情况，该模型已在独立队列中得到验证。本研究揭示了分别针对结直肠癌首次疗程与多疗程西妥昔单抗治疗的肿瘤诊断、初始应答预测及纵向应答预测所用潜在生物标志物的异质性，该成果最终有望为结直肠癌临床管理中的监测与干预策略提供参考价值。