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

Oncologist. 2013;18(7):865-75. doi: 10.1634/theoncologist.2013-0095. Epub 2013 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Molecular Targeted Therapy
  • Mutation
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / isolation & purification
  • Protein-Tyrosine Kinases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret / genetics*
  • Translocation, Genetic / genetics


  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • ROS1 protein, human