Emerging oncogenic fusions other than ALK, ROS1, RET, and NTRK in NSCLC and the role of fusions as resistance mechanisms to targeted therapy

Recent evidence has shown that gene fusions caused by chromosomal rearrangements are frequent events in the initiation and during progression of solid tumors, including non-small cell lung cancers (NSCLCs). Since the discoveries of ALK and ROS1 fusions in 2007 and the subsequent successes of pharmacological targeting for these fusions, numerous efforts have identified additional oncogenic driver fusions in NSCLCs, especially in lung adenocarcinomas. In this review, we will summarize recent advances in this field focusing on novel oncogenic fusions other than ALK, ROS1, NTRK, and RET fusions, which are summarized in other articles in this thematic issue. These novel gene fusions include neuregulin-1 (NRG1) fusions, MET fusions, fusion genes involving fibroblast growth factor receptor (FGFR) family members, EGFR fusions, and other rare fusions. In addition, evidence has suggested that acquisition of gene fusions by cancer cells can be a molecular mechanism of acquired resistance to targeted therapies. Most of the current data are from analyses of resistance mechanisms to EGFR tyrosine kinase inhibitors in lung cancers with oncogenic EGFR mutations. However, a few recent studies suggest that gene fusions can also be a resistance mechanism to ALK-tyrosine kinase inhibitors in lung cancers with oncogenic ALK fusions. Detection, validation, and pharmacological inhibition of these fusion genes are becoming more important in the treatment of NSCLC patients.