Recent advances in treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors with selective tyrosine kinase inhibitors have generated interest in identifying other cancers that could be approached with similar strategies. Cancers derived from follicular (papillary thyroid cancer; PTC) and parafollicular thyroid C cells (medullary thyroid cancer; MTC) represent paradigms of solid neoplasms in which tumor initiation events are well defined, and involve activating mutations of a receptor tyrosine kinase (TK). Germline mutations of the RET TK receptor confer predisposition to MTC with high penetrance. Chromosomal rearrangements linking the promoter and N-terminal domain of unrelated gene/s to the C-terminus of RET resulting in constitutively activated forms of the receptor (RET/PTC) are characteristic genetic changes of PTC, and are particularly prevalent in pediatric cancers and PTC arising after exposure to ionizing radiation. There are multiple lines of evidence that indicate that RET/PTC is a tumor-initiating event for PTC. RET-mediated transformation and dedifferentiation in vitro requires signaling via SHC-RAS-RAF-MEK. Recently, BRAF somatic mutations were reported in malignant melanomas, colorectal and ovarian cancers. We and others found that BRAF mutations are the most common genetic abnormality in PTC (~40%). Moreover, PTC either have mutations in RET/PTC, RAS or BRAF, with no overlap between them, and these altogether account for about 70% of tumors. These data provide compelling genetic evidence that thyroid cell transformation to PTC takes place through constitutive activation of effectors along the RET/PTC-RAS-BRAF signaling pathway. Kinase inhibitors with activity against RET are in preclinical or clinical development. Inhibition of RET-mediated signaling and cell growth can also be achieved with inhibitors of EGFR kinase, and preliminary evidence suggests that these compounds may interfere with RET/PTC-mediated transactivation of EGFR through heterodimerization. Despite their relative selectivity, most kinase inhibitors have activity against more than one target, and this property can potentially be used to advantage provided that key effectors that determine tumor phenotype are known.
22 - 24 Mar 2004
British Endocrine Societies