Researchers are seeking ways to overcome one of the greatest challenges of cancer—understanding why some patients do not respond to treatments. Some tumors exhibit multidrug resistance (MDR), which significantly limits the therapeutic options for patients. Now, a team at the Spanish National Cancer Research Centre (CNIO) has uncovered one of the causes of MDR, and a potential approach to overcome it in mice.

Their findings are published in EMBO Molecular Medicine in a paper titled, “Activation of the integrated stress response is a vulnerability for multidrug-resistant FBXW7-deficient cells.”

“FBXW7 is one of the most frequently mutated tumor suppressors, deficiency of which has been associated with resistance to some anticancer therapies,” wrote the researchers. “Through bioinformatics and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to MDR.”

Our findings “explain why many of the available therapies don’t work in certain tumors, and at the same time identify the weak point of these resistant cancers,” said Oscar Fernandez-Capetillo, head of the CNIO’s Genomic Instability Group and lead author of this research. “We now know that this vulnerability can be exploited using drugs that already exist.”

As the study shows, mutations that inactivate the function of a particular gene, FBXW7, “reduce the sensitivity to the vast majority of available therapies,” the authors wrote, but at the same time render tumor cells vulnerable to the action of a particular type of drug: those that activate the “integrated stress response” (ISR).

“FBXW7 is one of the 10 most frequently mutated genes in human cancers,” and is associated with “poor survival across all human cancers,” the authors added.

The researchers began by using CRISPR in mouse stem cells to search for mutations that generate resistance to anti-tumoral agents such as cisplatin, rigosertib, or ultraviolet light.

Mutations in the FBXW7 gene emerged early on, suggesting that this mutation could confer MDR.

Having established the link between FBXW7 deficiency and multi-resistance, the researchers looked for its cause. They found it in the mitochondria. The discovery of this mitochondrial stress was key to identifying strategies to overcome drug resistance in cells with FBXW7 mutations.

The authors have gone to show that tigecycline kills cells by hyperactivating the ISR.

“Our study, together with other recent works, indicate that activating the ISR could be a way to overcome chemotherapy resistance. 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,” said Fernandez-Capetillo.

“Our study reveals that while one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, it renders cells vulnerable to ISR-activating drugs,” concluded the researchers.

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