The ROS1 gene provides the blueprint for a protein known as a receptor tyrosine kinase. In its normal state, this protein is embedded in the cell membrane and is involved in signaling pathways that regulate processes like cell growth and differentiation. Its exact role is still under investigation, making it an “orphan receptor.”
When the ROS1 gene is altered by a mutation, it can lead to the production of a protein that functions abnormally, driving cells to multiply without control. These alterations are more commonly acquired during a person’s lifetime than inherited from a parent.
The Nature of ROS1 Gene Alterations
The most common and impactful type of change to the ROS1 gene is a structural rearrangement known as a gene fusion. This event occurs when a chromosome breaks apart, and a piece of the ROS1 gene detaches and connects with a fragment of an entirely different gene. This merging creates a new, hybrid gene that is not found in healthy cells.
This newly formed fusion gene produces a permanently activated ROS1 fusion protein. Normally, the ROS1 protein requires a specific signal to switch on and tell the cell to grow. The fusion protein, however, is constantly in the “on” position, bypassing the need for this external signal and instructing the cell to grow and divide uncontrollably.
While fusions are the primary type of ROS1 alteration linked to cancer, other, less frequent changes can also occur. These include point mutations, which are small-scale changes to the DNA sequence, and gene amplifications, where multiple copies of the ROS1 gene are created. These alterations can also contribute to abnormal cell behavior.
ROS1’s Role in Cancer Development
ROS1 alterations are most prominently associated with a specific type of lung cancer called non-small cell lung cancer (NSCLC), particularly the adenocarcinoma subtype. These genetic changes are identified in approximately 1% to 2% of all NSCLC cases. Patients with ROS1-positive NSCLC tend to be younger than the average lung cancer patient and often have little to no history of smoking.
This uncontrolled growth leads to the formation of tumors. Beyond NSCLC, ROS1 fusions have been found in a variety of other cancers, although less frequently. These include glioblastoma (a type of brain cancer), cholangiocarcinoma (bile duct cancer), ovarian cancer, and gastric cancer.
Identifying ROS1 Gene Changes
Detecting ROS1 gene alterations is a standard part of the diagnostic process for certain cancers, especially NSCLC, as the results directly influence treatment decisions. A tissue sample is obtained from the tumor through a biopsy. If a tissue biopsy is not feasible, a liquid biopsy may be used to look for tumor DNA in the blood.
One common technique is Fluorescence In Situ Hybridization (FISH), which uses fluorescent probes that bind to specific parts of the ROS1 gene. This allows scientists to visualize the gene under a microscope and see if it has been rearranged or fused with another gene.
Another method is Immunohistochemistry (IHC), which detects the presence of the abnormal ROS1 protein in tumor tissue, as an overabundance of this protein can indicate an underlying gene fusion. The most comprehensive approach is Next-Generation Sequencing (NGS), a technology that reads the precise sequence of a tumor’s DNA. NGS can identify all types of ROS1 alterations and often tests for many genetic biomarkers at once.
Treatment Strategies for ROS1-Driven Cancers
The discovery of ROS1 alterations led to targeted therapies, a significant advancement over chemotherapy. Unlike chemotherapy, targeted drugs are designed to specifically block the abnormal ROS1 protein driving the cancer’s growth. These ROS1 inhibitors can be highly effective at managing the disease.
Several ROS1 inhibitors have been approved by the U.S. Food and Drug Administration (FDA). Crizotinib was one of the first successful inhibitors, followed by newer agents like entrectinib and lorlatinib, which have shown improved efficacy and ability to treat cancer that has spread to the brain. More recently, repotrectinib has been developed to be effective against a broader range of ROS1 fusions and to overcome resistance.
Over time, cancer cells can develop new mutations that make them resistant to a ROS1 inhibitor, causing the drug to stop working. A doctor may then perform another biopsy to check for new mutations and switch the patient to a different inhibitor or explore other treatment options.