A ‘weak spot’ discovered that potentially makes multi-drug resistant tumors vulnerable

One of the greatest challenges facing cancer researchers is to understand why some patients don’t respond to treatments. In some cases, tumors exhibit what is known as multidrug resistance (MDR), which significantly limits the therapeutic options for patients. Researchers at the Spanish National Cancer Research Centre (CNIO) have discovered one of the causes of MDR, and a potential strategy to combat it. The work, which is mainly based on cell lines and is therefore still a long way from clinical use, is published in EMBO Molecular Medicine.

Our findings “explain why many of the available therapies don’t work in certain tumors, and at the same time identify the weak point of these resistant cancers,” explains Oscar Fernandez-Capetillo, head of the CNIO’s Genomic Instability Group and lead author of this research. “We now know that this vulnerability can be exploited using drugs that already exist.”

As the study shows, mutations that inactivate the function of a particular gene, FBXW7, “reduce the sensitivity to the vast majority of available therapies,” the authors write, but at the same time render tumor cells vulnerable to the action of a particular 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,” and is associated with “poor survival across all human cancers,” the authors add.

The study began by using the CRISPR technology in mouse stem cells to search for mutations that generate resistance to anti-tumoral agents such as cisplatin, rigosertib or ultraviolet light. Mutations in the FBXW7 gene emerged early on, suggesting that this mutation could confer MDR. 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 of the drugs available in this dataset.

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