Narrative review of molecular pathways of kinase fusions and diagnostic approaches for their detection in non-small cell lung carcinomas.

The discovery of actionable oncogenic driver alterations has significantly improved treatment options for patients with advanced non-small cell lung cancer (NSCLC). In lung adenocarcinoma (LUAD), approved drugs or drugs in clinical development can target more than half of these altered oncogenic driver genes. In particular, several gene fusions have been discovered in LUAD, including ALK , ROS1 , NTRK , RET , NRG1 and FGFR . All these fusions involve tyrosine kinases (TK), which are activated due to structural rearrangements on the DNA level. Although the overall prevalence of these fusions in LUAD is rare, their detection is extremely important, as they are linked to an excellent response to TK inhibitors. Therefore, reliable screening methods applicable to small tumor samples (biopsies and cytology specimens) are required in the diagnostic workup of advanced NSCLC. Several methods are at disposal in a routine laboratory to demonstrate, directly or indirectly, the presence of a gene fusion. These methods include immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), multiplex digital color-coded barcode technology or next-generation sequencing (NGS) either on DNA or RNA level. In our review, we will summarize the increasing number of relevant fusion genes in NSCLC, point out their underlining molecular mechanisms and discuss different methods for the detection of fusion genes.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-676). The series “Looking for Chimeras in NSCLC: Widen Therapeutic Options Targeting Oncogenic Fusions” was commissioned by the editorial office without any funding or sponsorship. Dr. MSM reports personal fees from Thermo Fisher, outside the submitted work. Dr. SS reports personal fees from MSD, personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Pfizer, personal fees from Thermo Fisher Scientific, outside the submitted work. Dr. LB reports grants from Sanofi, grants and personal fees from Roche, grants and personal fees from MSD, personal fees from Astra Zeneca, personal fees from Bayer, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Takeda, outside the submitted work. The other author has no other conflicts of interest to declare.
(2020 Translational Lung Cancer Research. All rights reserved.)