The Story of ROS1
An unwelcome mutation may drive normal cells to a cancerous destination.
Some rearrangements involve fusions due to DNA defecting from a cell or being shuffled in unexpected ways. A piece of DNA may move to another position on the cell or relocate to another cell. A part of the DNA may simply be lost. Sometimes a bit of DNA will break free from a cell, flip, and then reconnect like a microscopic trapeze artist.
One gene that goes to the dark side during a fusion is ROS1, a gene that codes for a tyrosine kinase receptor that plays an important part in a cell’s metabolism. (Tyrosine kinase receptors are located on the surface of cells and play a number of roles in cell growth, differentiation, proliferation, and metabolism.) ROS1 (also known as ROS, MCF3, and c-ros) was first identified as a potential cancer trigger in animal studies in 1982. Rearrangements of its DNA in human tissue were then discovered in malignant brain tumors in 1987, but any specific fusion partners that turned ROS1into a cancer promoter remained unknown until many years later. In 2007, some of those partners were identified in samples from non-small-cell lung cancer (NSCLC) tumors. ROS1had fused ·with genes that play important roles in immune response and in helping certain molecules travel between cells. Like trustworthy crossing guards who became corrupted, these fusions changed the normal signal patterns within cells and redirected “traffic” to a route that led to cancer.
The traffic analogy is fitting in this cancer scenario, since fusions that result in cancer are called “driver mutations.” These mutations alter the normal signals between molecules within cells, turning non-cancerous cells into malignant ones. Signals sent from the driver also prevent the body’s immune system from killing the malignant cells. Altered genes known as “passenger mutations” often accompany driver mutations in cancerous tumors. Although they are commonly found in certain types of malignancies, passenger mutations do not play a role in cancer progression and are of no concern regarding the treatment process. Implementing a therapy that targets these mutations would be akin to shooting at decoy ducks rather than real ones.
ROS1 fusions usually don’t overlap with other driver mutations, but they have a structure similar to the ALK oncogene -a well-documented culprit in NSCLC. The similarity between ROS1 and ALK helps explain why treatment of NSCLC with crizotinib (marketed under Xalkori) -a therapy developed to target ALK gene mutations -has also been found effective against tumors positive for a ROS1mutation. In one clinical study of crizotinib treatment, an NSCLC patient with a ROS1 fusion experienced a 57 percent tumor shrinkage. In a European study of crizotinib treatment, there was no progression of disease in 44 percent of NSCLC patients with ROS1fusions who ·were eligible for the assessment. Five patients in this group experienced a complete disappearance of their cancer. Similarly favorable outcomes were seen in a study involving cases in the U.S., Korea, and Australia, where crizotinib treatment reduced tumor size in 72 percent of patients who were ROS1-positive.
As a result of these promising findings, the Food and Drug Administration (FDA) recently approved crizotinib as a “breakthrough therapy” for the treatment of NSCLC cases with ROS1-positive tumors. The FDA created the breakthrough designation in 2012 to expedite the development and review of new medicines involved in the treatment of serious or life-threatening conditions, when preliminary evidence demonstrated a major improvement over existing therapies. (When a drug receives a breakthrough designation, the company producing the drug must work closely with the FDA to provide information supporting the designation.)
While ROS1 fusions in NSCLC tumors are relatively rare -about 2 percent of tumors overall -the cases add up when looking at it from a global perspective. Since Bo to 85 percent of the 1.5 million or more new lung cancer cases diagnosed each year are of the NSCLC type, an ROS1 fusion gene may be the key driver of more than 25,000 patients annually. ROS1chromosomal rearrangements have also been identified in cancers of the brain, ovary, gastrointestinal tract, and other body systems.
Some surprising patient demographics are associated with an increased likelihood of ROS1 fusion in NSCLC. Similar to patients with an ALK mutation, ROS1- positive tumors tend to occur in younger, non-smoking patients. This helps explain in part why patients with mutations of either ALK or ROS1may be responsive to the same targeted therapy, as sho·wn in studies of crizotinib. The common ground between ALK and ROS1has important implications for treatment decision-making. The similarity of their structure and of the demographics of affected patients means that there may be a similar series of events causing the mutation. These factors may include environmental exposures or genetic risk factors. Knowing these factors may help accelerate the identification of oncogenic mutations, which could allow an earlier diagnosis and initiation of treatment.
A major challenge remains for treatment of ROS1-positive patients: many of those who have a good response to crizotinib initially relapse over time, a phenomenon found with other cancer treatments as well. This failure may be due to interference from other gene mutations. Case in point: Certain mutations involving the KRAS gene appear to make cancer cells resistant to therapeutic attempts to block the cancer-triggering effects of ROS1. Identifying these genetic bushwhackers can be important for selecting the right candidates for therapy, and also may provide insights for developing more potent new ROS1 inhibitors to safeguard against such setbacks.
Molecular profiling to identify driver mutations such as ROS1 has become a standard part of the diagnosis and treatment decision-making in NSCLC and other cancer categories. But different types of screening technologies have yielded conflicting findings in some cases, so hopefully the technologies,vill become more refined and accurate over time. Screening is a critical part of the advancement of cancer therapy, since major gaps remain in our list of mutation suspects. In lung cancer, for instance, driver mutations have been determined in only about 60 percent of NSCLC cases. Does this mean that the other 40 percent do not have mutations, or that some mutations are slipping below the radar of current screening technologies? Better techniques for exploring the genetic universe in cancer will hopefully flush out more targets for therapy.