Buonocore, Preziosa (2015) RET therapeutic targeting in medullary thyroid carcinoma: molecular mechanisms of resistance. [Tesi di dottorato]

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Medullary Thyroid Carcinoma (MTC) is a rare C cell-derived thyroid tumor secreting calcitonin. MTC is sporadic in about 75% of cases and it is a component of the autosomal dominant "multiple endocrine neoplasia type 2" (MEN2) syndrome in about 25% of the cases. MTC represents a challenging clinical problem, as most MTC patients show distant metastases at time of diagnosis and chemotherapy and radiotherapy have limited efficacy. MTC is commonly associated to germline or somatic point mutations causing a gain-of-function of RET receptor tyrosine kinase. Given the oncogenic role of RET, it is feasible that specific targeting of this kinase could block tumor growth. Therefore, tyrosine kinase small molecule inhibitors (TKI) have been studied as potential novel agents for MTC treatment. The clinically most advanced RET TKIs are vandetanib (ZD6474) and cabozantinib (XL184), both recently registered for the treatment of locally advanced or metastatic MTC. However, cancer patients may be refractory to TKIs or develop secondary resistance after an initial response. Two major mechanisms have been envisaged to allow cancer cells to escape treatment with TKIs: 1) target up-regulation or mutations impairing drug binding; 2) activation of alternative pathways that bypass drug-mediated block. Thus, it is worth studying in preclinical models, molecular mechanisms of resistance to TKIs, since these informations can be thereafter clinically applied. In this dissertation, we have addressed molecular mechanisms of resistance to RET TKIs in cultured MTC cells. Our results show that MTC cells can develop resistance to chronic vandetanib treatment. Vandetanib-resistant cells show increased proliferation rate, anchorage-independent growth and in vivo tumorigenicity. Despite the absence of secondary RET genetic lesions, resistant cells escape RET inhibition and, differently from parental cells, they are able to grow even when RET is inhibited. Importantly, resistant cells feature hyper-activation of p90RSK kinase, a component of the MAPK (mitogen activated protein kinase) signaling cascade, a fact that mediates RET inhibition bypass. Accordingly, resistant cells are sensitive to p90RSK chemical blockade. In conclusion, gain of MAPK cascade signaling seems to be able to mediate escape from RET inibition in vitro, thus suggesting p90RSK as a promising molecular target to overcome resistance formation to RET TKIs.

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