A group of scientists from the Dana-Farber Cancer Institute, Massachusetts General Hospital, the Broad Institute of MIT and Harvard and the Ludwig Center at Harvard Medical School studied drug-resistant gastrointestinal stromal tumors (GISTs) to increase their understanding of what causes drug resistance in these tumors. Currently, most GISTs — a type of soft-tissue cancer — are caused by gene mutations that can be targeted with drugs, however, 10% to 20% of GISTs aren’t treatable with current medications.
In the study, investigators showed that changes in how genes are read by tumor cells, but aren’t caused by genetic mutations, can still lead to the development of GIST. Their findings have also indicated further areas of study that could make it possible to stop the development of tumors and treat these drug-resistant GISTs.
In order for a person’s DNA to fit inside their cells, it must wrap itself into loops with points called insulators. Researchers found that one of the insulators that prevents a cancer-causing gene known as FGF4 (fibroblast growth factor 4) is important to understanding drug-resistant GISTs. Another part of DNA has a switch that turns the FGF4 gene on and off. In healthy cells, FGF4 and the on/off switch are on separate loops. But in some forms of GIST, the insulator doesn’t work properly, allowing the loops to merge and turn on the cancer-causing FGF4 gene.
In this study, researchers worked with a form of GIST that had lost the function of the SDH enzyme complex, a key part in creating energy in a cell. These tumors also had an increased rate of DNA methylation, a process that adds chemical “tags” to DNA. The team found that too much DNA methylation destroys insulators in cells, leading to contact between on-switches and oncogenes, including the FGF4 gene and the KIT gene. The KIT gene is usually active in other forms of GIST.
To test their findings, investigators transplanted a human GIST into a mouse and showed that the model maintained the epigenetics of the parent tumor, including increased rates of DNA methylation and defective insulators. They also showed that tumor growth could be suppressed with fibroblast growth factor receptor FGF receptor inhibitors, both alone and with enzyme-inhibiting targeted therapy.
While targeted therapies can help SDH-deficient GIST patients, they typically become resistant to standard targeted therapies quickly. Researchers hope that these findings can open avenues for testing new therapies or repurposing old ones.