Progresses Toward Precision Medicine in <i>RET</i>-altered Solid Tumors.

Abstract

<i>RET</i> (rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but <i>RET</i> aberrations are involved in many pathologies. While <i>RET</i> loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, <i>RET</i> gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. <i>RET</i>-altered (<i>RET⁺</i> ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti-<i>RET</i> 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 <i>RET</i> 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 <i>RET</i> and its role in different kinds of tumors, clinical features of <i>RET⁺</i> tumors, clinically actionable genetic <i>RET</i> alterations and their diagnosis, and the available data and results of nonselective and selective targeting of <i>RET</i>.