Can New Structure of RET Inhibitors Capable of Suppressing Resistant in Non-Small-Cell Lung Cancer?

Abstract

In 2012, RET rearrangements are observed in 1-2% of Non-Small-Cell Lung Cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. Several compounds have been reported, including some traditional kinases inhibitors and the discovery of some new structure of natural products. Cabozantinib and vandetanib are multikinase inhibitors have been explored in the clinic for NSCLC patients. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects. Then, the discovery and clinical validation of highly potent selective RET inhibitors such as pralsetinib and selpercatinib demonstrating improved effificacy and a more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. In this review, we will highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.