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

Abstract

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.

Keywords: Clinical trials; Non-small cell lung cancer; RET; RET fusions; Thyroid cancer; Tissue-agnostic.

Fig. 1.

RET mechanisms in normal and oncogenic states. (1) Wild-type RET is a transmembrane protein with extracellular cadherin-like and cysteine-rich domains and an intracellular tyrosine kinase domain and isoform-specific tail. (2) Upon binding of the wild-type RET to a GFRα bound to a GDNF family ligand, RET homodimerizes, is autophosphorylated, and activates signaling through RAS, RAF, MEK, or ERK pathways. Ligands are color-coded (GDNF in red, NRTN in yellow, ARTN in green, and PSPN in blue), and respective GFRα receptors are color-matched. Calcium-binding is represented by bright green crosses and phosphorylation by the letter p in a yellow circle. (3) RET with oncogenic mutations, such as those indicated, is constitutively active. (4) Oncogenic RET with two of the most common fusions, CCDC6 and KIF58, is intracellular, undergoes ligand-independent dimerization, and is constitutively active.

Fig. 2.

RET inhibitor resistance mechanisms. The RET V804M/L gate-keeper mutations confer resistance to MKIs but are overcome by selective RET inhibitors. Solvent front mutations (e.g., RET G10S/C/R) confer resistance to selective RET inhibitors. Mutations or amplifications of MET or NTRK underlie off-target mechanisms of resistance to selective RET inhibitor therapy. EMT may also play a role in acquisition of RET inhibitor resistance.