Two new studies entitled “Systematic identification of signaling pathways with potential to confer anticancer drug resistance” and “RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis” identified new players and their downstream pathways that participate in the acquisition of resistance to current anti-cancer therapeutics by cancer cells. Both studies were published in the journal Science Signaling.
Cancer cells’ ability to resist and evade the action of drugs used in anti-cancer therapeutics is a crucial event underlying cancer mortality. Fully understanding the molecular pathways that sustain cancer cell survival in the presence of cytotoxic drugs is, therefore, urgent.
In these studies, a team of researchers at the Duke Cancer Institute screened several types of cancer cells, including melanoma, and traced the molecular pathways that allow resistance to arise. They confirmed several molecular players identified in previous studies but also discovered new unknown pathways. Notably, in both breast cancer and melanoma the authors identified the activation of Notch1 as a common pathway conferring resistance to tamoxifen (a standard therapeutics for early and advanced estrogen receptor positive breast cancers), in the case of breast cancer, and to MAPK inhibitors (short for mitogen-activated protein kinase) in melanoma cancer cells, with melanoma patients showing an increased expression of Notch1 pathway markers in their cancer cells.
Thus, the authors highlighted the potential of systematic screening strategies to identify new targets for potential therapeutic intervention in cancer-resistant patients.
Kris Wood, Ph.D., assistant professor of Pharmacology and Cancer Biology at Duke and leading author of the studies commented in a news release, “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. 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. 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.”
