Oregon researchers have used a new mass spectrometry technique to uncover a mutation that can cause leukemia. Their discovery is the first drug target uncovered by the method, which identifies abnormal cell-signaling proteins. The new technique, called protein mass spectrometry, could uncover other drug targets and reveal how drugs affect cancer cells.
The researchers were led by Brian Druker of the Oregon Health and Science University in Portland and Roberto Polakiewicz, chief scientific officer of Cell Signaling Technology in Danvers, MA. Druker’s lab focuses on a class of 90 signaling proteins called tyrosine kinases, which have been implicated in several kinds of cancer, including leukemia, breast cancer, and lung cancer. Mutations or other genetic mistakes can cause the activity of these proteins to go awry, leading to uncontrolled cell growth and division.
In the past, these proteins have been studied by sequencing the DNA of affected individuals and looking for common mutations. But cancer isn’t simple. “There are potentially hundreds of mutations in a given patient,” says Jeffrey Tyner, a postdoc in Druker’s lab. Only some of those mutations actually contribute to the cancer – and evaluating all of them is time-consuming.
In essence, DNA sequencing reveals only what the cell could do. Protein mass spectrometry, in contrast, provides a clearer picture of what the cell is doing. That’s why Cell Signaling Technology believes its approach is more efficient. “Proteomic [mass spectrometry] gives you the true readout of what’s going on in the cell,” says Mark Cobbold, a clinician scientist at the University of Birmingham, U.K.
Druker’s mass spectrometry study focused on acute myeloid leukemia, the most common form of the disease. And, while three common gene mutations are often to blame for it, in 30 to 50 percent of cases, the cause is unknown, says Tyner.
Druker hopes to duplicate his success in previous work on another form of leukemia, which led to the first successful molecularly targeted cancer drug, Gleevec (Imatinib). Approved for clinical use in 2001, the drug works by specifically binding to an abnormal tyrosine kinase protein and inhibiting it. The drug has worked wonders for some patients. “Druker is taking molecular medicine forward. Now he’s looking for other [leukemia targets] using a proteomics approach,” Cobbold says.
Looking at a cell’s actual molecular activity using mass spectrometry lets Druker avoid much of the guesswork in searching for cancer mechanisms. Instead of years, it took his lab just weeks to uncover a mutation in a gene for a kinase called JAK3 that causes the signaling molecule to be abnormally active. They found the mutation in a cell line, then verified the result in patients.