Researchers from the National Cancer Research Center (CNIO) have discovered in cell lines one of the causes of multi-drug resistance and an strategy Potential for fight it.
One of the great challenges of cancer is to understand why there is the patients What they don’t answer to treatments. In some cases, tumors introduce what is called multi-resistance, which significantly limits the treatment options for patients.
“Our result explains why in some tumors most of the usual therapies don’t workand at the same time identifies the weakness of these cancers resistant. Now we know that vulnerability May blow employing drugs that already exist”, explains Óscar Fernández-Capetillo, head of the CNIO group on genomic instability and main author of this research, which was published in the scientific journal “EMBO Molecular Medicine”.
As the study shows, mutations which inactivate the function of a specific gene, FBXW7, “reduce the sensitivity to the vast majority of therapies available”, and “at the same time, they return vulnerable the cells of tumor 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 in human cancers and is associated with poor survival in each of them.
A VERY COMMON MUTATION IN HUMAN CANCERS
The study began with search for mutations that generate resistance to antitumor agents such as cisplatin, rigosertib or ultraviolet light, using CRISPR technology in mouse stem cells. The mutations in the FBXW7 gene quickly emerged, suggesting that such a mutation could confer multi-resistance.
Bioinformatics analysis of databases such as the Cancer Cell Lines Encyclopedia (CCLE), with information on the answer more than a thousand lines human cancer cells to thousands of compounds, confirmed that the mutant cells son FBXW7 resistant to most drugs available in this dataset.
Regardless mutationsadditional analyzes in the Cancer Therapeutics Response Portal (CTRP) revealed that reduced levels FBXW7 expression were also associated with worse response to chemotherapy. The authors indeed propose to use the levels of FBXW7 as a biomarker to be able to to predict the patient’s response to drugs.
WITHOUT FBXW7, MITOCHONDRIA ARE STRESSED
established on relationship between FBXW7 deficiency and multi-resistance, the researchers sought their cause. They found her in the mitochondriacell organelles involved in metabolism and cellular respiration.
FBXW7-deficient cells showed excess protein in connection with mitochondriasomething that had already been seen associated to drug resistance. Detailed analysis of these organelles further revealed that the mitochondria of these multi-resistant cells appeared under a lot of stress.
This last data would be revealed key to be able to identify strategies that they overcome it drug resistance cells with mutations in FBXW7. The mitochondria are the rest of ancient bacteria, which fused billions of years ago with primitive eukaryotic cells; and if the antibiotics attack bacteriathe researchers wondered if a antibiotic kills a cancer cell too rich in mitochondria.
In the past, they have been identified antitumor properties in some antibioticsbut it was isolated cases and therefore potentially attributable to individual mutations -unknown- to patients.
Fernández-Capetillo and his group demonstrate that indeed the antibiotic tigecycline es toxic for cells deficient in FBXW7, which opens up a new line of research treat multi-drug resistance.
But probably even more relevant is the discovery of why this antibiotic has properties antitumor. The authors of the now published work show that tigecycline kill cells by means of the hyperarousal of the integrated stress response (ISR), and also show that other drugs capable of activating the ISR are also toxic to cells with mutations an FBXW7.
Many of these SRI activating drugs are oncological therapies in common clinical use today, and which until now were supposed to work in other mechanisms. However, this work reveals that part of its antitumor efficacy is due to its effect on Enable the SRI.
“Our studies, together with other recent ones, indicate that ISR activation may be a means of overcome the resistance to chemotherapy. However, There is a lot to do. 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.
The work has received funding from the Ministry of Science and Innovation, the Spanish Association Against Cancer (AECC) and the “La Caixa” Foundation, among others.