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Cetuximab (CTX), a monoclonal antibody against epidermal growth factor receptor, is being widely used for colorectal cancer (CRC) with wild‐type (WT) KRAS. However, its responsiveness is still very limited and WT KRAS is not enough to indicate such responsiveness. Here, by analyzing the gene expression data of CRC patients treated with CTX monotherapy, we have identified DUSP4, ETV5, GNB5, NT5E, and PHLDA1 as potential targets to overcome CTX resistance. We found that knockdown of any of these five genes can increase CTX sensitivity in KRAS WT cells. Interestingly, we further found that GNB5 knockdown can increase CTX sensitivity even for KRAS mutant cells. We unraveled that GNB5 overexpression contributes to CTX resistance by modulating the Akt signaling pathway from experiments and mathematical simulation. Overall, these results indicate that GNB5 might be a promising target for combination therapy with CTX irrespective of KRAS mutation. From gene expression data analysis and mathematical modeling combined with cell experiments, we found that DUSP4, ETV5, GNB5, NT5E, and PHLDA1 expressions are correlated with cetuximab (CTX) resistance. In particular, we discovered that inhibition of GNB5 can overcome CTX resistance irrespective of KRAS mutation. We further revealed that GNB5 can regulate CTX resistance by dominantly modulating Akt signaling. [ABSTRACT FROM AUTHOR]