RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives

Precision oncology informed by genomic information has evolved in leaps and bounds over the last decade. Although non-small cell lung cancer (NSCLC) has moved to center-stage as the poster child of precision oncology, multiple targetable genomic alterations have been identified in various cancer types. RET alterations occur in roughly 2% of all human cancers. The role of RET as oncogenic driver was initially identified in 1985 after the discovery that transfection with human lymphoma DNA transforms NIH-3T3 fibroblasts. Germline RET mutations are causative of multiple endocrine neoplasia type 2 syndrome, and RET fusions are found in 10–20% of papillary thyroid cases and are detected in most patients with advanced sporadic medullary thyroid cancer. RET fusions are oncogenic drivers in 2% of Non-small cell lung cancer. Rapid translation and regulatory approval of selective RET inhibitors, selpercatinib and pralsetinib, have opened up the field of RET precision oncology. This review provides an update on RET precision oncology from bench to bedside and back. We explore the impact of selective RET inhibitor in patients with advanced NSCLC, thyroid cancer, and other cancers in a tissue-agnostic fashion, resistance mechanisms, and future directions.