Background/Aim: Cetuximab in combination with chemotherapy is recommended as first-line therapy for metastatic colorectal cancer (mCRC) with wild-type RAS. However, drug resistance to cetuximab exists widely in mCRC and reduces the prognosis of patients. Although some genomic alterations have been demonstrated to drive acquired resistance to cetuximab, the overall compendium of inherent molecular mechanisms is still incomplete. Materials and Methods: Four liver metastasis biopsies were collected from two mCRC patients who were treated with cetuximab in combination with 5-fluororacil plus leucovorin and oxaliplatin (FOLFOX) regimen. Results: Transcriptomic analysis revealed global gene expression alterations between paired samples prior to treatment and after acquired resistance. Further bioinformatics analysis discovered differentially expressed protein-coding genes/lncRNAs/miRNAs, potential miRNA-mRNA regulatory networks and lncRNA-mRNA competing endogenous RNA network, which may be potential biomarkers or play roles during the process of acquired resistance to cetuximab. Conclusion: Our study contributes to deciphering the molecular mechanisms of acquired resistance to cetuximab.