Novel targets in non-small cell lung cancer: ROS1 and RET fusions

Abstract

The discovery of chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) has stimulated renewed interest in oncogenic fusions as potential therapeutic targets. Recently, genetic alterations in ROS1 and RET were identified in patients with NSCLC. Like ALK, genetic alterations in ROS1 and RET involve chromosomal rearrangements that result in the formation of chimeric fusion kinases capable of oncogenic transformation. Notably, ROS1 and RET rearrangements are rarely found with other genetic alterations, such as EGFR, KRAS, or ALK. This finding suggests that both ROS1 and RET are independent oncogenic drivers that may be viable therapeutic targets. In initial screening studies, ROS1 and RET rearrangements were identified at similar frequencies (approximately 1%-2%), using a variety of genotyping techniques. Importantly, patients with either ROS1 or RET rearrangements appear to have unique clinical and pathologic features that may facilitate identification and enrichment strategies. These features may in turn expedite enrollment in clinical trials evaluating genotype-directed therapies in these rare patient populations. In this review, we summarize the molecular biology, clinical features, detection, and targeting of ROS1 and RET rearrangements in NSCLC.

Keywords: Fusion oncogenes; Non-small cell lung cancer; RET; ROS1; Targeted therapy.

Figure 1.

Schematic diagram of ROS1 fusions in non-small cell lung cancer. (A): ROS1 tyrosine kinase domain (dark green), ROS1 transmembrane domain (blue), and coiled-coil domains (pink) in ROS1 fusion partners; KDELR2-ROS1 is not shown. (B): Reported frequencies of different ROS1 fusion partners. Not all studies included reverse transcription polymerase chain reaction primers against all fusion partners listed. Abbreviation: E, exon.

Figure 2.

A ROS1 break-apart fluorescent in situ hybridization (FISH) assay. FISH reveals separation of the 5′ ROS1 probe (green) from the 3′ ROS1 probe (red), indicative of a ROS1 rearrangement in a patient with non-small cell lung cancer. Size bar = 10 μm. Reprinted from [25] with permission [Bergethon, K et al: J Clin Oncol 2012;30:863—870 © 2013 American Society of Clinical Oncology. All rights reserved].

Figure 3.

Schematic diagram depicting RET fusions identified in non-small cell lung cancer. The RET tyrosine kinase domain (blue) is preserved in all fusions. Four different RET fusion partners are depicted: KIF5B, CCDC6, TRIM33, and NCOA4. KIF5B is the most common fusion partner, with seven different KIF5B-RET fusion variants described to date. Abbreviation: TM, transmembrane.

Figure 4.

Models of RET rearrangements. (A): Schematic representation of the RET proto-oncogene (left). RET activation typically involves ligand binding, interactions with a coreceptor, and homodimerization leading to formation of a multiprotein complex (right). (B): Schematic representation of a KIF5B-RET fusion (left). The coiled-coil domain of KIF5B promotes ligand-independent homodimerization of RET, leading to constitutive activation of downstream growth signaling. Abbreviations: CC, coiled-coil domain; GFL, glial cell line-derived neurotrophic factor family ligand; GFRα, GDNF family receptor α; KIF5B, kinesin family member 5B; P, phosphorylated tyrosine residue; RET, rearranged during transfection; TK, tyrosine kinase; TM, transmembrane.