Protein Kinase inhibitors for the treatment of thyroid cancer: molecular mechanisms of resistance
Magesh, Muthu (2011) Protein Kinase inhibitors for the treatment of thyroid cancer: molecular mechanisms of resistance. [Tesi di dottorato] (Inedito)
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Though most types of thyroid cancer are cured by surgery and adjuvant radio- iodine therapy and TSH suppression, patients with radio-iodine refractory thyroid carcinoma as well as with medullary thyroid carcinoma, a neuroendocrine malignancy that does not express iodine transporter, are difficult to treat because of the lack of effective systemic treatment. Therefore, there is an urgent need of novel therapeutic measures for these patients. Thyroid cancer is frequently associated to the oncogenic conversion of protein kinases such as RET (medullary thyroid cancer) and BRAF (papillary and undifferentiated thyroid cancer). Therefore, protein kinase small molecule inhibitors (PKI) have been considered as promising novel agents for the treatment of thyroid carcinoma. Compounds that revealed good RET and BRAF activity both in clinical (vandetanib for RET) and in pre-clinical (vemurafenib for BRAF) settings have been identified. Recently, vandetanib was approved for patients with medullary thyroid carcinoma and vemurafenib was approved for patients affected by melanoma. Cancer patients may be refractory to PKI or develop secondary resistance after an initial response. Two general mechanisms can explain resistance: i) the presence of mutations in the kinase that blocks binding to the PKI; ii) the oncogenic switch to another pathway that rescues cancer cells from kinase blockade. In this dissertation, we have addressed mechanisms of resistance in the case of RET PKI (for the treatment of medullary thyroid carcinoma) and BRAF PKI (for the treatment of radio-iodine refractory thyroid carcinoma). Here we show that: i) ponatinib is a novel RET PKI and is able to overcome RET resistance mediated by mutations in RET V804 and Y806; ii) thyroid cancer cells escape treatment with vemurafenib by switching to another signaling pathway and that inhibitors of the IGF1R/PI3K/AKT signaling cascade may be exploited to overcome resistance of thyroid cancer cells lines to BRAF PKI.
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