Spanish researchers discover ‘weak point’ that makes resistant tumors vulnerable

Researchers from the National Cancer Research Center (CNIO) discovered one of the causes of multidrug resistance in tumors and a potential strategy to combat it, which is one of the great challenges of cancer as it severely limits treatment options for patients.

The work “explains why many usual therapies do not work in certain tumors, and at the same time identifies the weak point of these resistant cancers”, explains Óscar Fernández-Capetillo, lead author of the research published in EMBO molecular medicine. “We now know that this vulnerability can be exploited using drugs that already exist.“.

According to the study, mutations that inactivate the function of a specific gene, FBXW7, reduce susceptibility to the vast majority of available therapies and at the same time render tumor cells vulnerable to the action of a specific type of drug: those that activate the “integrated stress response (ISR)”.

“FBXW7 is one of the ten most frequently mutated genes in human cancers”, and is associated with “poor survival in all of them”, add the authors.

The work explains why many therapies do not work in certain tumors and at the same time identifies the weak point of these resistant cancers

The study began by searching for mutations generating resistance to antitumor agents such as cisplatin, rigosertib or ultraviolet light, using CRISPR technology in mouse stem cells. Mutations in the FBXW7 gene quickly appeared, suggesting that this mutation could confer multi-resistance.

Bioinformatics analysis of databases such as Encyclopedia of Cancer Cell Lines (CCLE), with information on the response of over a thousand human cancer cell lines to thousands of compounds, confirmed that FBXW7 mutant cells are resistant to most drugs available in this data set.

Our studies, together with other recent ones, indicate that activating ISR could be a way to overcome resistance to chemotherapy

Oscar Fernandez-Capetillo

CNIO researcher

Regardless of the mutations, further analysis revealed that reduced levels of FBXW7 expression were also associated with a poorer response to chemotherapy.

After establishing the relationship between FBXW7 deficiency and multi-drug resistance, researchers looked for its cause. They found it in the mitochondriacell organelles involved in metabolism and cellular respiration.

This latter information would be essential to be able to identify strategies to overcome drug resistance in cells with mutations in FBXW7. Mitochondria are the remnants of ancient bacteria that billions of years ago fused with primitive eukaryotic cells. And if antibiotics attack bacteria, could an antibiotic kill a cancer cell that is too rich in mitochondria?

Fernández-Capetillo’s team shows that the antibiotic tigecycline is toxic for cells deficient in FBXW7, which opens up a new avenue of research to fight against multidrug resistance.

But even more relevant is the discovery of why this antibiotic has antitumor properties.. The authors of the work show that tigecycline kills cells by hyperactivating the integrated stress response (ISR), and further demonstrate that other drugs capable of activating the ISR are also toxic to cells with mutations in FBXW7.

It should be noted that many of these SRI-activating drugs are cancer therapies in common clinical use today, and until now have been assumed to work through other mechanisms. However, the present work reveals that part of its antitumor efficacy is due to its ISR activating effect.

“Our studies, together with other recent ones, indicate that activating the ISR could be a way to overcome resistance to chemotherapy. However, there is still a lot to do,” says Fernández-Capetillo.

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