RET Fusion: Joining the Ranks of Targetable Molecular Drivers in NSCLC

Abstract

The era of precision medicine has resulted in the identification of a number of genomic alterations that can be targeted with novel therapies. In lung adenocarcinomas, a histology structure that accounts for nearly 50% of all cases of lung cancer, and a number of genomic targets have been linked with effective targeted therapies. For patients with advanced-stage lung adenocarcinomas, molecular testing is now a standard part of diagnostic workup; for patients that have specific driver molecular events, targeted therapies have resulted in substantial improvement in efficacy without excessive toxicity. RET gene fusions are present in approximately 1% to 2% of NSCLC. It is emerging as a new targetable driver for this population. Despite sensitivity to platinum-based chemotherapy and conflicting small reports regarding the efficacy of immune checkpoint inhibitors, there have been limited treatment approaches for this subset of patients. Multiple nonselective RET tyrosine kinase inhibitors exhibited modest anti-RET activity with an increased off-target toxicity profile that often required dose interruption, reduction, or treatment cessation. Recently, novel selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) have exhibited promising clinical activity with low adverse effect profile in early clinical trials. These new agents are poised to represent a new hope for this special subgroup with unmet needs.

Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN): a retrospective analysis of patients treated through an access program

“…Rearranged during transfection (RET) gene fusions have been identified in approximately 10-20% of papillary thyroid cancers and in up to 1-2% of non-small cell lung cancers (NSCLCs), primarily in adenocarcinomas and less commonly in other tumor types. [1][2][3][4][5] The RET proto-oncogene codes for a transmembrane receptor-tyrosine kinase (RTK); the constitutive activation of the intracellular kinase domain through RET chimeric fusion proteins favours tumor cell growth and spread. 5,6 Moreover, as is the case with other oncogenic driven NSCLCs [e.g.…”

Identification and Validation of Noncanonical RET Fusions in Non–Small-Cell Lung Cancer through DNA and RNA Sequencing

“…Oncogenic RET rearrangements have been found in 1-2% non-small-cell lung cancers (NSCLCs) 4 . The rearrangements often generate fusions of the RET 3'-kinase domain (exon [12][13][14][15][16][17][18] to diverse and heterologous 5'-upstream partner genes, with the breakpoints commonly located within the intron 11 of RET 5,6 . The chimeric proteins gain oncogenic properties either by ligand-independent dimerization when the upstream partner contains a dimerization domain or by aberrant constitutive expression of RET when the partner is regulated by a ubiquitous promoter 7,8 .…”

“…Despite their rarity, RET fusions define a distinct molecular subtype of NSCLC patients J o u r n a l P r e -p r o o f who benefit modestly from multikinase inhibitors with RET activity and immunotherapy 12,13 . Recently, two highly selective RET inhibitors, namely selpercatinib and pralsetinib, have demonstrated remarkable responses and efficiencies in advanced RET-fusion positive NSCLCs and received U.S. Food and Drug Administration approval 14,15 .…”

Targeted therapy of RET fusion-positive non-small cell lung cancer

“…Having demonstrated great activity in ALK fusion-positive (89), It has been approved as a first-line treatment for metastatic ALK fusion-positive NSCLC after crizotinib treatment (90). Previous studies have shown that Alectinib strongly inhibits RET, FLT3, CHEK2, and LTK but not VEGFR (91). Therefore, it may also be a potentially effective treatment option for RET fusion-positive NSCLC.…”