One of the great challenges in cancer is understanding why there are patients who do not respond to treatment. In some cases, the tumors present what is known as multi-resistancewhich significantly limits the therapeutic options for patients.
Researchers at the National Cancer Research Center (CNIO) have discovered one of the causes of this multidrug resistance and a potential strategy to combat it. It’s mostly a job based on cell lines and, therefore, still far from clinical application, which is published in EMBO Molecular Medicine.
The work explains why many of the usual therapies do not work on some tumors. Furthermore, we now know that this vulnerability can be exploited using drugs that already exist.
This 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”, comments Oscar Fernandez Capetillo, lead author of the study. “Furthermore, we now know that this vulnerability can be exploited with drugs that already exist,” he adds.
As the study shows, mutations that inactivate the function of the gene called FBXW7 “reduces sensitivity to the vast majority of available therapies,” the authors write. On the other hand, these same genetic changes make tumor cells vulnerable to the action of a specific type of drug: those that activate the “integrated stress response” (ISR).
A very common mutation in human cancers
“FBXW7 is one of the 10 most frequently mutated genes in human cancers,” the authors add.
The study began with the search for mutations that generate resistance to antitumor agents such as cisplatin, rigosertib or ultraviolet light, using the CRISPR Technology in mouse stem cells. Mutations in the FBXW7 gene appeared early, suggesting that they may confer multidrug resistance in these cells.
In addition, the team analyzed databases that store information about the response of more than 1,000 human cancer cell lines to thousands of compounds. This bioinformatics analysis confirmed that cells carrying mutations in FBXW7 are resistant to most of the registered drugs.
The team analyzed databases that store information about the response of more than 1,000 human cancer cell lines to thousands of compounds.
Additional analyzes revealed that reduced levels of FBXW7 expression are associated with a poorer response to chemotherapy.
The researchers found that FBXW7-deficient cells show a excess mitochondria-related proteins, the cellular organelles involved in metabolism and cellular respiration, −something that had already been linked to drug resistance−. A detailed analysis of these organelles also revealed that the mitochondria of these multidrug-resistant cells appear to be under a lot of stress.
Mitochondria are the remains of ancient bacteria that merged with primitive eukaryotic cells billions of years ago. The study authors found that the antibiotic tigecycline is toxic to FBXW7-deficient cells.
Anti-tumor properties had already been identified in certain antibiotics in the past, but these were isolated cases. However, the current finding opens a new avenue of research to deal with multidrug resistance.
Drugs that act to exacerbate stress
Fernández-Capetillo and his team show that tigecycline kills cells by hyperactivating the integrated stress response (ISR) and also demonstrate that other drugs capable of activating the ISR are also toxic to cells with FBXW7 mutations.
Many of these SRI activating drugs are Oncological therapies of common clinical use today and that until now were supposed to work by other mechanisms. However, the present work reveals that part of its antitumor efficacy is due to its effect on the activation of the ISR.
“Our studies – in addition to other recent ones – indicate that activating the ISR may be a way to overcome resistance to chemotherapy. However, much remains to be done. Which drugs are the best and most activating the SRI? Which patients would benefit most from this strategy? Trying to answer these questions is what we intend to dedicate ourselves to in the immediate future”, says Fernández-Capetillo.
Reference:
Laura Sanchez-Burgos et al. “Activation of the Integrated Stress Response is a vulnerability for multidrug-resistant FBXW7-deficient cells.” EMBO Molecular Medicine (2022)