Efficacy of erbB specific tyrosine kinase inhibitors in thyroid carcinoma cells

Abstract

The expression and activation of epidermal growth factor receptor (EGFR) and related erbB receptors is associated with thyroid tumorigenesis. Besides an enhanced proliferation, cell survival and angiogenesis, activation of erbB receptors may be associated with resistance to cytotoxic drugs. In our study we analyzed the expression of erbB receptor family members in thyroid carcinoma cells. Furthermore, we studied whether inhibition of erbB receptors may influence proliferation and increase sensitivity towards chemotherapeutic drugs in undifferentiated thyroid carcinoma cells. We found that FTC133, SW1736 and HTh74 thyroid carcinoma cells expressed high levels of EGFR, while HTh7 and C643 cells showed no EGFR expression. ErbB2 expression was moderat in SW1736, HTh7 and C643 cells and negative in FTC133 and HTh74 cells. ErbB4 was expressed in all cell lines except C643. Treatment with 1.0–5.0µM of the tyrosine kinase inhibitor CL387785 (CL) resulted in an inhibition of FTC133, HTh74 and C643 cells. SW1736 and HTh7 cells were not inhibited but unexpectedly showed increased proliferation with low concentrations (0.1–1.0µM CL) perhaps due to autocrine stimulation processes. All cell lines were insensitive to cisplatin up to concentrations of 2.0µg/ml. Doxorubicin showed a slight but significant inhibitory effect at 0.2–1.0µM. Gemcitabine (0.02–0.05µg/ml) was effective in FTC133, SW1736 and C643 cells. Neither CL nor the additionally used tyrosine kinase inhibitor PD153035 (PD) had an effect on cisplatin, doxorubicin or gemcitabine sensitivity. In contrast, camptothecin exhibited an effective inhibition of FTC133 and SW1736 cells (0,02µg/ml). Interestingly, the lower sensitivity of HTh7 cells to camptothecin could be increased by tyrosine kinase inhibition with 0.5µM CL or 0,2µM PD. In conclusion, inhibition of tyrosine kinases may be an effective approach to decrease proliferation of chemo-insensitive thyroid carcinoma cells. Treatment with tyrosine kinase inhibitors may thus become clinically relevant for treatment of undifferentiated thyroid carcinomas.