A novel radiosensitizing therapy for anaplastic thyroid cancers

摘要

The anaplastic thyroid carcinoma has a poor therapeutic response and leads to high mortality. The nonreceptor tyrosine kinase, c-ABL, along with one of the p53 downstream targets, is critical in the regulation of the cell cycle and radiation-induced cell response. To discover a novel therapy for anaplastic thyroid carcinomas, we investigated the therapeutic potential of a c-ABL-specific tyrosine kinase inhibitor, STI571. Western blot analysis demonstrated high expression levels of c-ABL in anaplastic thyroid cancer cell lines (mutated p53). These cell lines showed marked inhibition of cell growth after treatment with STI571. In contrast, the growth of papillary thyroid cancer cell lines (wild-type p53) had low levels of c-ABL and was not inhibited by STI571. Colony formation assay showed that STI571 enhanced the effect of ionizing radiation in anaplastic cancers, but not in differentiated cancers. The human anaplastic cancer tumors implanted into immunocompromised mice were irradiated by the STI571 and radiation combination therapy. In contrast, tumor growth did not change with radiation alone, compared with an untreated control group. In conclusion, c-ABL is overexpressed in anaplastic thyroid carcinoma cells, and selective suppression of c-ABL activity by STI571 is a potential molecular targeting therapy in combination with radiation therapy for p53-defective or -mutated thyroid carcinomas.