Abstract
BRAF V600E is the most common genetic alteration in thyroid cancer and is indicative of a relatively poor prognosis. A selective inhibitor of BRAF V600E has been proposed as a novel treatment for patients with thyroid cancer exhibiting BRAF V600E mutations. However, this inhibitor has demonstrated a limited therapeutic effect. In the present study, possible adaptive mechanisms of resistance of thyroid cancer cells to the specific BRAF V600E inhibitor, PLX4032, were investigated. MTT assays were performed to determine the anti-proliferative efficiencies and half maximal inhibitory concentration (IC50) of inhibitory treatments. The level of phosphorylated ERK was used to evaluate the activity of the mitogen assisted protein kinase (MAPK) pathway. Flow cytometry was performed to evaluate the rate of apoptosis. The IC50 measurements of PLX4032 in K1 and BCPAP cells were 0.550 and 1.772 µM, respectively. Co-treatment with an endothelial growth factor receptor (EGFR) inhibitor decreased the IC50 of PLX4032 to 0.206 µM, and prolonged the inhibitory effect of PLX4032 in K1 cells. In cells treated with PLX4032 alone, the MAPK pathway was reactivated after 24 h. However, the addition of an EGFR inhibitor suppressed this reactivation and increased the rate of apoptosis. In summary, the present study demonstrated that thyroid cancer harboring the BRAF V600E mutation was resistant to a selective BRAF inhibitor due to reactivation of the MAPK pathway. Co-treatment with an EGFR inhibitor increased antitumor efficacy and suppressed resistance to the BRAF V600E inhibitor.