About ROS1 Fusions

ROS1 is an enzyme that is coded by the ROS1 gene. The enzyme has receptor tyrosine kinase (RTK) activity, that is, it is one of several critical regulators of normal cellular activity.

A gene fusion is when a gene abnormally breaks off at a certain point and fuses with another gene to form a hybrid gene product composed of 2 originally distant genes. Gene fusions are also known as gene rearrangements as the order or arrangement of the genes on the chromosome changes. These fusions or rearrangements may happen as a result of several abnormal genetic events such as deletions, duplications, inversions or translocations. Abnormally fused genes can lead to cancer initiation and drive its growth, as these fusion events might juxtapose two genes, which independently might not be oncogenic, but upon fusion can spur each other’s activity, driving abnormal cellular activity.

A ROS1 gene fusion is the result of aberrant intra-chromosomal (same chromosome breaks and re-joins abnormally) or inter-chromosomal (different chromosomes break apart and re-join abnormally) rearrangements that result in the ROS1 gene being juxtaposed with a variety of partner genes. These fusions of the ROS1 gene are oncogenic, and have been found to occur in a variety of cancers: glioblastoma (GBM), non-small cell lung cancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, etc. So far, 11 fusion partner genes have been identified for ROS1 fusions in non-small cell lung cancer, including CD74-ROS1, SDC4-ROS1,EZR-ROS1, and SLC34A2-ROS1. ROS1 fusions account for only 1-2% of all diagnoses in all cancer types it is found in, making this molecular subset a relatively rare one.

ROS1 fusions may be detected by a variety of techniques from clinical bio-specimens, such as Fluorescent In-Situ Hybridization (FISH), Immuno Histochemistry (IHC), Reverse Transcriptase- Polymerase Chain Reaction (RT-PCR), and next-generation sequencing. With the recent FDA approval of crizotinib for the first-line treatment of non-small cell lung cancer patients, ROS1 fusions are increasingly becoming one of the top 3 molecular alterations tested for in lung cancer, along with EGFR and ALK testing. It is important that everyone diagnosed with cancer insist upon molecular testing of their tumors to determine if their cancer is driven by an actionable gene that can be treated with currently available targeted therapies. Don’t guess, test!

ROS1 fusions in NSCLC respond very well to targeted therapy with Crizotinib (Xalkori). The U.S. Food and Drug Administration (FDA) recently approved Crizotinib for the first line treatment of ROS1-rearranged metastatic NSCLC. ROS1 fusions in most cancers other than lung cancer are treated with chemotherapy. There are currently several targeted treatments under evaluation for the treatment of ROS1-fusion positive patients, either in the first-line setting or after resistance to crizotinib sets in.