Doug Lauffenburger and colleagues at MIT took a converse approach. Rather than trying to figure out why some patients with EGFR mutations don’t response to EGFR inhibitors, Lauffenburger wanted to know why the drug worked in so many people without the mutation.
His team began with two sets of cancer cells, those that are resistant to the drug and others that are sensitive to it. The team measured various biochemical and biophysical properties of the cells, including an analysis of how molecules move around the cell, how well receptors bind to molecules called growth factors, and the activation of molecular pathways downstream from the EGFR receptor.
Using those measurements, the team constructed a model of each cell type, looking for the major differences between the two. They found multiple variables, but one stood out; cells that were sensitive to the drug had a slower uptake of receptors into the cell. While it’s not exactly clear how this makes the cells respond to the drug, Lauffenburger says, the location of the receptor when it binds its target effects which downstream chemical pathways are activated.
The findings, if they are replicated in patients, point toward a new way to determine which patients would respond to EGFR inhibitors. Researchers are now trying to figure out how to devise a screening test that would work well in patients. (Assessing the behavior of a particular receptor in a patient’s cancer cells is too difficult for a test to be used routinely in patients.)
In addition, Lauffenburger’s team found they could make cancer cells sensitive to the drug by adding another drug that inhibits one of the downstream pathways implicated in the model. This class of drugs, called MEK inhibitors, is currently in clinical trials for different kinds of cancer.
“Both studies have generated new insights into combinational therapy that may enhance targeted therapies,” says Dan Gallahan, deputy director of the National Cancer Institute’s Division of Cancer Biology. “The results underline the complexity of the disease, but also show that if we critically understand what’s going on, we can figure out how to intervene.” Clinical studies are needed to confirm the findings, he adds, but “these studies lay the scientific groundwork to do that.”