New combination of drugs can defeat drug-resistant cancer cells

Cancer cells can adapt and develop resistance to chemotherapy drugs, making it difficult to eradicate tumors. A new study conducted by researchers at Brigham and Women's Hospital suggests that a combination of three drugs, including a new class of glucose-6-phosphate dehydrogenase inhibitors, could overcome the resistance cross-therapy The results of the study are published today in Scientific signage.

"It's only recently that we have begun to understand the full complexity of the failure of chemotherapy," said Aaron Goldman, Ph.D., professor of medicine at the Bioengineering Division of Brigham. "The drugs themselves are part of the problem in terms of where the resistance comes in. The resistance is not just intrinsic to the cells."

The researchers used computer models, in vitro experiments, in vivo animal models and clinical explants, ex vivo models of human tumors to probe the metabolic processes underlying tolerance to chemotherapy drugs.

In keeping with the Warburg effect – a widely accepted paradigm for drug resistance – researchers have found that cancer cells absorb excess glucose, causing glycolytic pathways to saturate. But unlike the Warburg effect, the researchers found an increase in mitochondrial activity, indicating a high consumption of cellular oxygen.

With the help of a mathematical modeling, Goldman and his team discovered that a combination of three drugs administered during a time-sensitive progression sensitized cancer cells. In addition to this new class of drugs, clinically available drug combinations could also be used to fight resistance, Goldman said.

Researchers recognize that they do not yet fully understand the plasticity of cancer cells that allows them to acquire new metabolic phenotypes and become resistant to drugs. In the future, researchers hope to use mathematical modeling and machine learning to develop more and more accurate treatment regimens to inform new cancer treatments.

"We mathematically model biological frameworks that will allow us to predict drug sequences," Goldman said. "We do not just collect drugs, we develop combinations that rationally attack resistance."