Reduced expression of CYLD promotes cell survival and inflammation in gefitinib-treated NSCLC PC-9 cells: targeting CYLD may be beneficial for acquired resistance to gefitinib therapy.

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non-small-cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR-TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR-TKI resistance remains elusive. Here, we found CYLD was upregulated in PC-9 cells, whereas downregulated in PC-9 acquired gefitinib-resistant (PC-9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC-9/GR cells than that in PC-9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin-6, transforming growth factor-beta and tumor necrosis factor-alpha, which may contribute to acquired resistance of PC-9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC-9/GR cells downregulated CYLD expression, enhanced subsequent CYLD-dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib-resistant treatment in NSCLC.