Oncology Central

New screening technology identifies pathways to cancer drug resistance

Researchers from Duke Cancer Institute (NC, USA) have identified key steps in the development of cancer cell resistance to lethal therapies. The findings, published in two separate December papers in Science Signaling, provide clear targets for the blocking of these pathways and thus potentially ensuring that current therapies are consistently effective.

Lead author, Kris Wood (Duke Cancer Institute) commented: “Clinical resistance to anticancer therapies is a major problem. 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.”

The team focused on the specific stages of the development of drug resistance in melanoma, breast cancer and myelofibrosis.

“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 explained.

A broad survey was carried out of the known cell signaling pathways that hold the potential to trigger drug resistance in cancer cells when activated. With the use of the screening technology developed by the team, they were able to corroborate the results of previous drug resistance studies in addition to identifying previously undescribed resistance pathways.

Importantly, the resistance mechanisms identified by the Duke Cancer Institute team in the laboratory were also clinically relevant, appearing in tumor cells from patients who had already become resistant to therapies.

“Interestingly, the mechanisms are quite similar among all three of the cancer types,” Wood explained. “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 the analysis of myelofibrosis, the investigators tracked a pair of signaling pathways downstream of RAS. It was demonstrated that when activated, these pathways suppress cell death and therefore promote resistance to standard-of-care targeted drugs. In the second paper in Science Signaling, the authors suggest that targeting of pathways downstream of RAS could 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 concluded.

Source: Duke medicine press release




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