Precious Gene: The Application of RET-Altered Inhibitors

Abstract

The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.

Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical

“…Selpercatinib has exhibited robust and durable anti-tumor activity in medullary thyroid carcinoma (MTC) cases harboring RET mutations [ 165 ]. Importantly, it has been associated with a favorable safety profile [ 167 ], although some common adverse reactions have been observed, such as gastrointestinal discomfort, elevated liver enzyme levels, prolonged QT time, abdominal pain, hypertension, and fatigue [ 168 ]. However, recent reports have identified mutations in RET G810R/S/C/V that have the potential to result in treatment failures, despite not affecting ATP binding [ 113 , 114 , 162 ].…”