Cetuximab (Ctx), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) for colorectal cancer treatment, often faces diminished clinical efficacy due to acquired resistance driven by EGFR mutations. Here, we investigated the molecular mechanisms underlying this mutation-induced drug resistance and developed a mechanism-based strategy to restore the binding affinity of Ctx to EGFR mutants. Through molecular dynamics simulations and free energy perturbation calculations, we discovered that most resistant mutations primarily alter the electrostatic properties of the binding interface. Focusing on two key mutations, EGFR K489E and I491M, we rationally designed two Ctx variants-Ctx