Researchers at the National Cancer Research Center (CNIO) have discovered one of the causes of multi-drug resistance in tumors and a potential strategy to combat it, which constitutes one of the great challenges in cancer as it significantly limits therapeutic options for the patients.
The work “explains why many of the usual therapies do not work in some tumors, and at the same time identifies the weak point of these resistant cancers,” says 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, the mutations that inactivate the function of a specific gene, FBXW7, reduce sensitivity to the vast majority of available therapies and at the same time make 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 of the therapies do not work in some tumors and at the same time identifies the weak point of these resistant cancers
The study began with the search 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 emerged, suggesting that this mutation could confer multi-resistance.
Bioinformatic analysis of databases such as the Cancer Cell Line Encyclopedia (CCLE), with information on the response of more than a thousand human cancer cell lines to thousands of compounds, confirmed that FBXW7 mutant cells are resistant to most drugs available in this dataset.
Our studies, added to 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 poorer response to chemotherapy.
Having established the relationship between FBXW7 deficiency and multi-resistance, the researchers looked for its cause. They found it in the mitochondriathe organelles of the cell involved in metabolism and cellular respiration.
This last piece of information would be key to being able to identify strategies that overcome drug resistance in cells with mutations in FBXW7. Mitochondria are the remnants of ancient bacteria, which billions of years ago merged with primitive eukaryotic cells; And if antibiotics attack bacteria, could an antibiotic kill a cancer cell too rich in mitochondria?
Fernández-Capetillo’s team shows that the antibiotic tigecycline is toxic to cells deficient in FBXW7, which opens a new avenue of research to tackle multi-resistance.
But even more relevant is the finding 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 ISR-activating drugs are cancer therapies in common clinical use today, and that until now it was assumed that they worked through other mechanisms. However, the present work reveals that part of its antitumor efficacy is due to its effect in activating the ISR.
“Our studies, added to other recent ones, indicate that activating the ISR could be a way to overcome resistance to chemotherapy. However, much remains to be done,” says Fernández-Capetillo.