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Researchers Map Paths to Cancer Drug Resistance

Findings may offer way to keep current therapies effective

Researchers at the Duke Cancer Institute in Durham, North Carolina, have identified key events that prompt certain cancer cells to develop resistance to otherwise lethal therapies.

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

The new findings were published December 23 in two papers in the journal Science Signaling.

“Clinical resistance to anticancer therapies is a major problem,” said lead author Kris Wood, PhD. “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, and using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” Wood added.

In the first paper, Wood and his colleagues conducted a 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 the cancer types,” Wood said. “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 has not been widely acknowledged previously.”

Wood said that in myelofibrosis, the researchers tracked a pair of separate signaling pathways downstream of 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 paper, the researchers suggest 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 to design drug combinations that work together to block or delay resistance,” Wood said.

Source: EurekAlert; December 23, 2014.

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