Mapping New Ways to Block Cancer Pathways and Keep Drugs Effective

A team of researchers led by Duke Cancer Institute has identified key events that prompt certain cancer cells to develop resistance to otherwise lethal therapies.

By mapping the specific steps that melanoma, breast cancer, and myelofibrosis cells use to become resistant to drugs, the researchers now have much better targets for blocking those pathways and keeping current therapies effective.

The findings were published in two papers in the Dec. 23, 2014 issue of the journal Science Signaling.

“Clinical resistance to anticancer therapies is a major problem,” says lead author Kris Wood, PhD, assistant professor of pharmacology and cancer biology at Duke. “The most logical way to solve the problem is to understand why tumor cells become resistant to drugs and develop strategies to thwart these processes.”

“In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant. Using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” Wood says.

Wood and colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger resistance to drugs. Using this screening technology, they were able to corroborate the results of earlier drug-resistance studies, while also finding new pathways that had not previously been described.

The new mechanisms they identified in the laboratory were also clinically relevant, appearing in tumor cells from patients who had grown resistant to therapies.

“Interestingly, the mechanisms are quite similar among all three of these cancer types,” Wood says. “In breast cancer and melanoma, our findings suggest the same Notch-1 pathway as a potential driver of resistance to a wide array of targeted therapies—a role that had not been widely acknowledged previously.”

Wood says that in myelofibrosis, the researchers tracked a pair of separate signaling pathways downstream from an important signaling molecule called RAS. When activated, these pathways promote resistance to current standard-of-care targeted drugs by suppressing cell death. In the second Science Signaling paper, the researchers suggested that targeting the pathways downstream of RAS may sustain the potency of current therapies.

“Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Wood says.