Why Are Certain Cancer Cells Resistant to Therapy?

Researchers seek better targets for blocking events that lead to drug resistance.

Understanding the steps cancer cells take to become resistant to treatment may maintain the effectiveness of current therapies, according to a recent study.

In a pair of papers published December 23, 2014, in the journal Science Signaling, researchers mapped the specific steps cells of melanoma, breast cancer, and myelofibrosis take to achieve drug resistance. The work could provide better targets to block these steps and maintain the effectiveness of current therapies.

"Clinical resistance to anticancer therapies is a major problem," lead author Kris Wood, PhD, said in a press release. "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.”

The study utilized a broad survey of known cell-signaling pathways that can trigger drug resistance when activated. Utilizing screening technology, the researchers corroborated the findings from previous drug-resistance studies and found new previously undetected pathways.

These new mechanisms were found in the tumor cells of patients who had grown resistant to current 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."

In myelofibrosis, the study followed a pair of different signaling pathways that are downstream from the important signaling molecule RAS. These pathways promote resistance to the current standard-of-care targeted drugs through the suppression of cell death when activated.

Targeting the pathways that are downstream of RAS may maintain the effectiveness of current therapies, the researchers noted.

"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 said.