Beyond ALK and ROS1: RET, NTRK, EGFR and BRAF gene rearrangements in non-small cell lung cancer

Abstract

The discovery of gene rearrangements involving the receptor tyrosine kinase genes ALK and ROS1 has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve ALK and ROS1, fusions involving other kinases including RET, NTRK, EGFR and BRAF are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients.

Keywords: BRAF; EGFR; NTRK; RET; non-small cell lung cancer (NSCLC).

Figure 1

Schematic representation of oncogenic fusion proteins. (A) Wild-type proto-oncogene schematic of a RTK (above) and fusion protein produced by an in-frame gene rearrangement (below); (B) schematic of normal signaling by RTK, which occurs in a ligand-dependent manner to activate downstream signaling pathways such as MEK and PI3K; (C) fusion oncogene signaling occurs in a ligand independent manner, and can involve fusions that span the membrane (left) or are fully intracellular (right). Figure is adapted and modified from reference (8). TM, transmembrane domain; RTK, receptor tyrosine kinase.