Scientists identify potential “weak spot” in drug-resistant cancers

Scientists in Spain have uncovered a mechanism behind why some cancer patients don’t respond well to treatments – and more importantly, found a “weak spot” that could be targeted by existing drugs.

Frustratingly, many cancer patients don’t respond well to treatments like chemotherapy. A condition known as multidrug resistance (MDR) can seriously limit the options available to them. But exactly what factors contribute to MDR – and how it might be countered – remains murky.

In the new study, researchers at the Spanish National Cancer Research Centre (CNIO) have identified one way that MDR can occur. The team started by examining genes that might play a role in allowing cancers to become drug resistant, using CRISPR gene-editing in mouse stem cells. In doing so, a gene known as FBXW7 quickly caught their attention.

FBXW7 is among the most common gene mutations in cancer, and has been linked to poor survival rates in patients. When the team cross-checked datasets, they found that mutations to the FBXW7 gene bestowed cells with a resistance to most drugs in the dataset, with lower levels of FBXW7 expression linked to worse responses to chemotherapy.

On closer inspection, the researchers uncovered a potential root cause. Cells that were deficient in FBXW7 had higher levels of mitochondrial proteins, a feature that’s been associated with drug resistance.

But importantly, the team also identified a way to turn this strength into a weakness. The excess proteins seemed to be stressing the mitochondria of the cancer cells, and a drug called tigecycline was found to be toxic to them by activating a process called integrated stress response (ISR). Follow-up tests with other drugs that activate ISR proved promising as well.

“Our study, together with other recent works, indicate that activating the ISR could be a way to overcome chemotherapy resistance,” said Oscar Fernandez-Capetillo. lead author of the study. “However, much work remains to be done. Which drugs activate the ISR best and most strongly? Which patients would benefit most from this strategy? Attempting to answer these questions is what we aim to do in the immediate future.”

The research was published in the journal EMBO Molecular Medicine.

Source: CNIO

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