RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

SIMPLE SUMMARY: Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that shows targetable mutations and gene fusions in a few types of cancers. Multiple kinase inhibitors, which target RET kinase, show little efficiency in tumors with RET gene alterations. Therefore, the new RET-specific inhibitors have been developed. Selpercatinib and pralsetinib showed high effectiveness in clinical trials, but their efficacy was shown to be reduced by the occurrence of secondary alterations such as resistance mutations or activation of different signaling pathways. New drugs that could be used in patients with secondary mutated RET gene are under investigation and show promising results. ABSTRACT: Mutations and fusions of RET (rearranged during transfection) gene are detected in a few common types of tumors including thyroid or non-small cells lung cancers. Multiple kinase inhibitors (MKIs) do not show spectacular effectiveness in patients with RET-altered tumors. Hence, recently, two novel RET-specific inhibitors were registered in the US and in Europe. Selpercatinib and pralsetinib showed high efficacy in clinical trials, with fewer adverse effects, in comparison to previously used MKIs. However, the effectiveness of these new drugs may be reduced by the emergence of resistance mutations in RET gene and activation of different activating signaling pathways. This review presents the function of the normal RET receptor, types of molecular disturbances of the RET gene in patients with various cancers, methods of detecting these abnormalities, and the effectiveness of modern anticancer therapies (ranging from immunotherapies, through MKIs, to RET-specific inhibitors).