‘Weak point’ discovered that makes drug-resistant tumors vulnerable

DAILYPHARMA | 21.07.2022 – 13:12

Researchers from the National Center for Oncological Research (CNIO) uncovered one of the causes of multi-drug resistance and a potential strategy to combat ita. It is a work mainly based on cell lines −therefore still far from clinical−, which is published in EMBO Molecular Medicine.

Our result “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, leader of the Instability group. Genomics of the CNIO and main author of this research. “Now we know that this vulnerability can be exploited using drugs that already exist.”

As the study shows, mutations that inactivate the function of a specific gene, FBXW7, “reduce sensitivity to the vast majority of available therapies” – write the authors -, and “at the same time make tumor cells vulnerable to the action of a specific gene”. 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 study began by looking for mutations that generate 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 the Cancer Cell Lines Encyclopedia (CCLE), with information on the response of over a thousand human cancer cell lines to thousands of compounds, has confirmed that mutant cells FBXW7 are resistant to most drugs available in this dataset.

Regardless of the mutations, further analysis in the Cancer Therapeutics Response Portal (CTRP) revealed that reduced levels of FBXW7 expression were also associated with a poorer response to chemotherapy – the authors actually suggest using the levels of FBXW7 as a biomarker to predict patient response to drugs.

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

FBXW7-deficient cells showed an excess of mitochondria-bound proteins, which was previously associated with drug resistance. Detailed analysis of these organelles further revealed that the mitochondria of these multi-resistant cells appeared to be under severe stress.

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?

In the past, antitumor properties had already been identified in certain antibiotics, but these were isolated cases and therefore potentially attributable to unknown individual mutations of the antibiotics. the patients. Fernández-Capetillo and his group show that the antibiotic tigecycline is indeed toxic for cells deficient in FBXW7, which opens up a new avenue of research to deal with multi-resistance.

But probably even more relevant is the discovery of why this antibiotic has antitumor properties. The authors of the now published paper 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 bearing the FBXW7 mutations.

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 his efficiency antitumor is due to its activating effect of ISR.

“Our studies, together with other recent ones, indicate that activating the ISR could be a way to overcome resistance to chemotherapy. However, much remains to be done. What are the drugs that best and most activate the ISR? Which patients would benefit the most from this strategy? Trying to answer these questions is what we intend to focus on in the immediate future,” says Fernández-Capetillo.

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