Spanish researchers unlock the mystery of multidrug resistance

By The Science Advisory Board staff writers

July 25, 2022 -- A team from the Spanish National Cancer Research Centre (CNIO) has determined that mutations that inactivate the function of a particular gene, FBXW7, reduce the sensitivity to the vast majority of drugs and result in multidrug resistance (MDR), according to a study published July 21 in the journal EMBO Molecular Medicine. The mutations also render tumor cells vulnerable to drugs that activate the integrated stress response.

Using CRISPR technology in mouse stem cells to search for mutations that generate resistance to antitumoral agents such as cisplatin, rigosertib, or ultraviolet light, the researchers came across FBXW7 early on. Bioinformatic analysis of the Cancer Cell Line Encyclopedia (CCLE) and more than a thousand human cancer cell lines to thousands of compounds confirmed FBXW7 mutant cells are indeed resistant to most of the cancer drugs available.

However, reduced levels of FBXW7 expression were also associated with a worse response to chemotherapy and FBXW7 levels could be used as a biomarker to predict patient response to drugs. It turned out FBXW7-deficient cells showed an excess of mitochondrial proteins, which has previously been found to be associated with drug resistance. Also, the mitochondria appeared to be under a lot of stress, which became the key to identifying strategies to overcome drug resistance.

The research team found the antibiotic tigecycline is toxic to FBXW7-deficient cells and opens up a new avenue for treating MDR. Tigecycline kills cells by hyperactivating the integrated stress response, and other drugs can do the same. In other words, activating the integrated stress response could be the mechanism to overcome chemotherapy resistance.

Future research will focus on which drugs activate the integrated stress response the best and most strongly as well as which patients would benefit the most from the strategy.

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