Molecular mechanisms in thyroid cancer
There are four major types of thyroid cancer: well-differentiated papillary (PTC) and follicular (FTC) carcinoma, undifferentiated anaplastic carcinoma (ATC), and neural-crest derived medullary carcinoma (MTC). In the past two decades, some genetic lesions associated with these tumor types have been unveiled, with mutations in RET and BRAF, RAS and PPARγ, RAS, BRAF and PI3K/AKT, and RET, associated to PTC, FTC, ATC and MTC, respectively. PTC and FTC patients are treated by surgical resection, adjuvant radioiodine treatment and thyroid hormone replacement. However, some of them may have recurrent disease with loss of responsiveness to radioiodine. MTC patients, particularly those with RET-mutated sporadic tumors, are often incurable because the cancer has already metastasized before being diagnosed. ATC, though extremely rare, has a dismal prognosis with an average survival of less than 1 year. This has suggested molecularly targeted therapy as one possibility for patients with iodine refractory thyroid cancer. A major problem in exploiting this possibility is our only partial understanding of the molecular lesions that alone or in combination are associated to the various types of thyroid cancer. Nonetheless, it is feasible that therapeutic targeting of some specific protein or lipid kinases might be potentially beneficial for the treatment of thyroid cancer. Multitarget RET inhibitors that function in the nM range are undergoing clinical testing in patients with MTC and PTC. These compounds are multi-target and share the ability of inhibiting not only RET but also the VEGFRs, thereby exerting both anti-tumor and anti-angiogenic activity. BRAF or MEK inhibitors are promising, alone or in combination with other pathway inhibitors, for the treatment of PTC or ATC; importantly, these compounds are more effective in BRAF mutant than BRAF wild type cancer cells. These approaches exploit the so called oncogene addiction, i.e. the dependency of cancer cells on the genetic lesions that have initiated the transformation process. A second possibility has emerged for treating cancer and referred to as non-oncogene addiction. This second approach exploits the dependency that cancer cells have on proteins that are not mutated per se but still essential for their viability. Some specific mitotic kinases, such as PLK1, can be promising targets to exploit the non-oncogene addiction phenomenon in ATC cells. One problem that could emerge with the use of pathway inhibitors is molecular resistance formation. This may be caused by regulatory circuits that compensate for the blocked kinase or by mutations in the targeted kinase that abrogate drug binding. Understanding regulatory pathways as well as mutations causing resistance is crucial to further develop targeted approaches for thyroid cancer treatment.