One of the biggest challenges facing cancer researchers One is to understand why some patients do not respond to treatment. In some cases, tumors exhibit so-called multidrug resistance (MDR), which greatly limits treatment options for patients. Researchers at the Spanish National Cancer Institute (CNIO) have discovered one of the causes of MDR, as well as potential strategies to combat it. The work is mainly based on cell lines, so it is still a long way from clinical application, published in EMBO Molecular Medicine .
Our findings “explain why many of the available therapies do not work in some tumors, while finding identify the weaknesses of these drug-resistant cancers,” explains Oscar Fernandez-Capetillo, head of the Genome Instability Group at CNIO and lead author of the study. “We now know that this vulnerability can be exploited using drugs that already exist.”
As the study shows, The mutation authors write that it inactivates the function of a specific gene, FBXW7, “reducing sensitivity to the vast majority of available therapies,” but at the same time leaves tumor cells vulnerable to a specific type of drug: those that activate the “combined stress response” ( ISR).
Very common mutation in human cancer
” FBXW7 is one of the 10 most commonly mutated genes in human cancers,” and is associated with “low survival in all human cancers,” the authors added.
The study began by using CRISPR technology in mouse stem cells to find mutant cisplatin that confer anti-tumor resistance , rigosertib or UV light. Mutations in the FBXW7 gene appeared very early, suggesting that this mutation can confer multidrug resistance. Bioinformatics analysis of databases such as the Cancer Cell Lines Encyclopedia (CCLE), along with information on the responses of more than a thousand human cancer cell lines to thousands of compounds, confirmed that FBXW7 mutant cells possessed the potential for most of the drugs available in this dataset. Drug resistance.
Regardless of mutation, further analysis in the Cancer Therapy Response Portal (CTRP) revealed that FBXW7 expression levels Decreasing is also associated with poorer response to chemotherapy. In fact, the authors suggest using FBXW7 levels as a biomarker to predict patient response to drugs.
Without FBXW7, mitochondria are stressed
After confirming FBXW7 After the link between deficiency and multidrug resistance was discovered, researchers set out to find its cause. They found it in mitochondria, organelles involved in metabolism and cellular respiration.
FBXW7-deficient cells exhibit excess mitochondrial protein, which has previously been implicated in drug resistance . However, detailed analysis of these organelles further revealed that the mitochondria of these multidrug-resistant cells appeared to be under a lot of stress.
An antibiotic effective against tumor cells
The discovery of this mitochondrial stress will be key to identifying strategies to overcome drug resistance in FBXW7 mutant cells. Mitochondria are remnants of ancient bacteria that fused with primitive eukaryotic cells billions of years ago; so if antibiotics attack bacteria, can antibiotics kill cancer cells with too many mitochondria?
In fact, anti-tumor properties of certain antibiotics have been identified in the past, but these are isolated cases , and therefore an unknown individual mutation that may be attributable to the patient. Fernandez-Capetillo and his team have demonstrated that the antibiotic tigecycline is indeed toxic to FBXW7-deficient cells, opening a new avenue of research to address multidrug resistance.
By overactivating the stress response Drugs that work
but may More importantly, it was discovered why this antibiotic has antitumor properties. The authors of the just-published paper show that tigecycline kills cells by overactivating the integrated stress response (ISR), and further demonstrate that other drugs capable of activating ISR are also toxic to FBXW7-mutated cells.
It is worth noting that many of these ISR-activating drugs are commonly used clinical tumor therapies today, and so far Until now, they have been thought to work through other mechanisms. However, current studies suggest that part of their antitumor efficacy is due to their effect on activating the ISR.
“Our study and other recent work suggest that activation of the ISR may be a way to overcome chemoresistance However, there is still a lot of work to be done. Which drugs will activate the ISR best and most strongly? Which patients will benefit most from this strategy? Trying to answer these questions is our near-term goal,” Fernandez-Capetillo said.
More information: Laura Sanchez-Burgos et al., Activation of the integrative stress response is a vulnerability in multidrug-resistant FBXW7-deficient cells, EMBO Molecular Medicine
(2022). DOI: 10.15252/emmm.202215855
citation
: Discovery may predispose MDR “Weakness” under attack (22 July 2022) Retrieved 1 September 2022 from https://medicalxpress.com/news/2022-07-weak-potentially-multi-drug-resistant-tumors.html
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