CEMIP promotes gefitinib resistance in lung cancer with EGFR-mutation possibly through forming a stable complex CEMIP/c-MYC

While gefitinib greatly improves the prognosis of lung cancer patients with epidermal growth factor receptor (EGFR) mutation, its inevitable resistance severely diminishes therapeutic efficacy. Cell migration-inducing protein (CEMIP) might interact with cellular MYC proto-oncogene (c-MYC) to synergistically drive gefitinib resistance. However, the mechanism by which CEMIP/c-MYC regulates gefitinib resistance in LUAD remains unknown. The gefitinib-acquired resistance (AR) cell line PC9GR was established by gradual dose-escalation induction. CEMIP expression was up-regulated in PC9GR cells, suggesting the positive corelationship might exsit between CEMIP expression and gefitinib resistance. Similarly, overexpressing CEMIP in PC9 cells not only increased IC₅₀ value of gefitinib but also enhanced the proliferation, migration and tolerance to gefitinib. In contrast, downregulating the expression of CEMIP in PC9GR cells partially restored gefitinib sensitivity and reduced malignant phenotypes. Furthermore, c-MYC promoted transcriptional activity through binding to the promoter region of CEMIP. Rescue assays demonstrated that reducing the expression of c-MYC downregulated the IC₅₀ value of Gefitinib, migration and tolerance of gefitinib in PC9 OE cells, while overexpressing c-MYC reversed these malignant phenotypes in PC9GR shCEMIP cells. Subcutaneous xenograft model also supported that the expression of CEMIP positively correlated to c-MYC in tumor tissues. Mechanistically, protein docking simulations and Co-IP assays indicated that CEMIP directly interacted with c-MYC via its 1-177aa domain to form the CEMIP/c-MYC complex. Furthermore, CHX chase assays showed that CEMIP and c-MYC mutually stabilized the expression of both proteins. The elevated CEMIP/c-MYC axis accelerates EMT to enhance cell migration, thereby contributing to the acquisition of gefitinib resistance in LUAD.