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.