Review: biological implications of oncogenic rearrangements in non-small cell lung cancer

The identification of oncogenic rearrangements that generate new active fusion proteins in lung cancer has revolutionized the diagnostic and therapeutic approach of these malignancies. Usually, gene fusions involve genes that encode tyrosine kinases that, as a result, become constitutively active and promote tumor growth. Functionally active fusion proteins are usually strong oncogenes, and most are actionable targets. Tumors harboring fusion proteins show “oncogene addiction” and are sensitive to drugs that target the corresponding fusion oncoprotein. Thus, in recent years, the molecular characterization of non-small cell lung cancer (NSCLC) has helped shape a new diagnostic and therapeutic paradigm: in addition to their utility as biomarkers for the purposes of diagnosis, prognosis, and the identification of disease progression, “driver” fusion proteins can provide actionable targets for therapy. Indeed, molecular testing for specific genetic alterations, such as ALK, ROS1, RET and NTRK gene fusions, is now in the routine clinical practice for newly diagnosed advanced NSCLC to define the best targeted therapeutic approach for each patient. In addition, the continuous identification of new “targetable” gene fusions in NSCLC will implement diagnostic procedures where the simultaneous testing of gene fusions through high-throughput screening will become the standard diagnostic procedure. In this Review, we discuss the impact of oncogenic fusions in NSCLC pathogenesis, including ALK, ROS1, RET and NTRK. We also provide a full description of each fusion in terms of biological and clinical characteristics as well as the implication of their diagnosis.