RET kinase inhibitors for the treatment of RET-altered thyroid cancers: Current knowledge and future directions

RET gain-of-function mutations are the most common drivers in medullary thyroid carcinoma, while RET fusions are identified in 5–10% of papillary thyroid carcinomas. Thus, RET plays a major role in the tumorigenesis of thyroid neoplasia, making it a valuable therapeutic target. Over a decade ago, multikinase inhibitors (MKIs) were first shown to have variable degrees of anti-RET activity. Despite some clinical efficacy in RET-altered thyroid cancers, significant off-target activity of MKIs led to marked toxicities limiting their use. More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. However, these treatments are non-curative, and emerging evidence suggests that patients who progress on therapy acquire mutations conferring drug resistance. Thus, the quest for a more definitive treatment for advanced, RET-altered thyroid cancers continues. This year we celebrate the 30^th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.