Progresses toward precision medicine in RET-altered solid tumors

RET (rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but RET aberrations are involved in many pathologies. While RET loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, RET gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. RET-altered (RET^þ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti-RET activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective RET inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of RET and its role in different kinds of tumors, clinical features of RET^þ tumors, clinically actionable genetic RET alterations and their diagnosis, and the available data and results of nonselective and selective targeting of RET.