Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer

Abstract

Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions.

Keywords: RET fusion; ROS1 fusion; multiplex diagnosis system; oncogene fusion; tyrosine kinase inhibitor (TKI).

Figure 1

Pie charts showing the proportion of LADC harboring aberrations in driver oncogenes. Data from patients in East Asia (Japan, Korea, and China) and from those of European descent were generated by summarizing the results from previous reports (2-4). LADC, lung adenocarcinoma.

Figure 2

Schematic diagram showing RET fusion proteins in LADC. The domains are highlighted in different colors: RET tyrosine kinase domain (orange), RET transmembrane domain (TM; green), and coiled-coil domain (blue) in fusion partners. LADC, lung adenocarcinoma.

Figure 3

Schematic diagram showing ROS1 fusions in LADC. The domains are highlighted in different colors: ROS1 tyrosine kinase domain (orange), ROS1 transmembrane domain (TM; green), and coiled-coil domain (blue) in fusion partners. LADC, lung adenocarcinoma.

Figure 4

Schematic diagram of other fusion proteins in non-small cell lung cancer. (A) Fusion proteins in LADC. TM, transmembrane domain; (B) fusion proteins in IMAs. EGF, EGF-like domain; (C) FGFR fusion proteins in SQLC. The domains are highlighted in different colors: tyrosine kinase domain (orange), transmembrane domain (TM; green), immunoglobulin-like domain (dark green), coiled-coil domains (blue). LADC, lung adenocarcinoma.