Researchers from the Barts Cancer Institute at Queen Mary University of London have identified a way to reverse resistance to a group of cancer drugs, called kinase inhibitors, in leukemia cells. By rewiring the inner workings of cancer cells, the team was able to prime leukemic cells for susceptibility to treatment in the laboratory.
Kinase inhibitors are a type of targeted medicine that blocks chemical messengers (enzymes) called kinases in cells. Kinases activate proteins in cells that are required for a variety of normal cell functions, including metabolism, growth, division, and survival; however, kinases can become dysregulated in cancer, helping cancer cells grow and survive.
Although kinase inhibitors have shown success in treating certain types of tumors, many cancers fail to respond or develop resistance against these targeted drugs. In this study, Professor Pedro Cutillas and his team discovered that it was possible to overcome resistance to kinase inhibitors in leukemia cells by manipulating the cellular pathways that cells use to survive.
The Biotechnology and Biological Sciences Research Council, Barts Charity and Cancer Research UK funded the research, and the results were published today in Scientific signage.
Cut Alternate Routes
Kinase inhibitors work by blocking components of different signaling pathways that cancer cells use to grow and survive. However, in the same way that satellite navigation devices suggest an alternative route to reach a destination in the event of a road closure; cells can learn to use other pathways to perform a function when a drug blocks their usual pathway. These alternative pathways, or “intrinsic resistance,” offset the effects of the drug and can prevent the drug from killing the cancer cell.
Building on previous work that investigated drug resistance mechanisms that target kinases, the team first treated leukemia cell lines with an experimental drug (GSK2879552) to block an enzyme called LSD1. LSD1 has a role in regulating gene expression in cells.
Blocking LSD1 inhibited the activity of one signaling pathway (called the PI3K/AKT pathway), but activated another signaling pathway (called the MEK/MAPK pathway) that the leukemic cells were forced to use to survive .
As leukemia cells now depended on the MEK/MAPK pathway for survival, the team used a second drug – a kinase inhibitor called trametinib – to block the pathway. By doing this, the team cut off all escape routes from the cells and they were killed.
Here, we found that intrinsic resistance to kinase inhibitors could be overcome by coercing kinase networks into drug-sensitivity tolerant pathways. By targeting LSD1 with one drug, we rewired the kinase network and left the cancer cells unable to escape treatment with the second drug, trametinib.”
Pedro Cutillas, Study Leader, Professor, BCI Center for Cancer Genomics and Computational Biology
The team used the same sequential treatment approach to treat blood cells taken from patients with acute myeloid leukemia (AML) and found that the drug combination was effective in killing around 50% of AML samples.
Further experiments revealed that certain genetic changes and characteristics within cancer cells influenced the cells’ sensitivity or resistance to sequential treatment. These characteristics may represent biomarkers that could help predict the subpopulation of patients most likely to respond to this type of treatment.
Drug resistance is a major obstacle in cancer treatment and is responsible for the majority of cancer deaths. Trametinib has shown limited efficacy against leukemia in early phase clinical trials; however, this early-stage research has identified a means by which drug resistance against these kinase inhibitors can be reversed and potentially prevented.
Professor Cutillas added: “Instead of treating cancers with two or more drugs at the same time, as has been the main approach in previous drug combination research, our work suggests that sequential treatment with one inhibitor to create a new pathway addiction, followed by treatment with an inhibitor against the newly activated pathway may be an effective treatment strategy in leukemia.”
The team hopes that this approach can be translated into the clinic in the future, to increase the effectiveness of drugs that, by themselves, have not shown significant clinical benefit. The team also wants to explore whether the findings can be applied to other types of cancer besides leukemia.