“Clinical resistance to anticancer therapies is a major problem,” said lead author Kris Wood, Ph.D., 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, and using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” Wood said.
“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 Science Signaling 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 design drug combinations that work together to block or delay resistance,” Wood said.
Martz et al. Systematic identification of signaling pathways with potential to confer anticancer drug resistance.Sci Signal. 2014;7(357):ra121. doi: 10.1126/scisignal.aaa1877 [Abstract]
Winter et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7(357):ra122. doi: 10.1126/scisignal.2005301 [Abstract]