RET kinase alterations in targeted cancer therapy

The rearranged during transfection (RET) gene encodes a protein tyrosine kinase. RET alterations by point mutations and gene fusions were found in diverse cancers. RET fusions allow abnormal expression and activation of the oncogenic kinase, whereas only a few of RET point mutations found in human cancers are known oncogenic drivers. Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors (TKIs) with RET inhibitor activity. These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations. Recently, two potent and selective RET TKIs, pralsetinib (BLU-667) and selpercatinib (LOXO-292), were developed. High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials, demonstrating the RET dependence in human cancers harboring these RET lesions. Pralsetinib and selpercatinib were effective in inhibiting RET^V804L/M gatekeeper mutants. However, adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RET^G810 residue have been found, pointing to the need for the development of the next-generation of RET TKIs.