One of the biggest challenges cancer researchers face is understanding why some patients are unresponsive to treatments. In some cases, the tumors exhibit what is known as multi-drug resistance (MDR), which significantly limits treatment options for patients. The mechanisms of cellular resistance are multiple and range from membrane transporters (MDRG-1), to detoxifying / antioxidant enzymes (GST-1, gGCL, NQO-1, etc.), to mutations in the target proteins of the drug itself. This problem has been at the heart of cancer research for at least 30 years. Researchers from the Spanish National Cancer Research Center (CNIO) have uncovered one cause of MDR and a potential strategy to fight it. As the study shows, mutations that inactivate the function of a particular gene, FBXW7, reduce sensitivity to the vast majority of available therapies, but at the same time make cancer cells vulnerable to the action of another type of drugs: those that activate the “integrated stress response” (ISR).
FBXW7 / hCDC4 is one of the 10 most frequently mutated genes in human cancers and is associated with poor survival in all human cancers. It is basically a tumor suppressor, that is, it works by suppressing cell proliferation as does the famous p53 protein, and participates in the functions of the proteasome. The ubiquitin proteasome system (UPS) performs its protein breakdown function by three enzymes: the ubiquitin activating enzyme (E1), ubiquitin conjugator enzyme (E2) and ubiquitin ligase (E3). Among these, ubiquitin ligase E3 is the most critical component of the UPS capable of specifically recognizing proteins to complete their ubiquitination, a sort of “tagging” to direct their destruction. FBXW7 is just the ubiquitin ligase E3. The study began using CRISPR technology in mouse stem cells to look for mutations that generate resistance to anticancer agents such as cisplatin, rigosertib or ultraviolet light. Mutations in the FBXW7 gene emerged early, suggesting that this mutation could confer MDR.
Bioinformatics analysis of databases such as the Cancer Cell Line Encyclopedia (CCLE), with information on the response of over a thousand human cancer cell lines to thousands of compounds, has confirmed that FBXW7 mutant cells are resistant to most of the drugs available in this set of data. Regardless of the mutations, further analyzes in the Cancer Therapeutics Response Portal (CTRP) revealed that reduced levels of FBXW7 expression were also associated with a worse response to chemotherapy. Indeed, the authors suggest using FBXW7 levels as a biomarker to predict patient response to drugs. Having established the link between FBXW7 deficiency and multi-resistance, the researchers searched for its cause. They found it in mitochondria, our cellular powerplants. Cells deficient in FBXW7 showed an excess of mitochondrial proteins, a kind of inner engulfment which was previously found to be associated with drug resistance.
However, detailed analysis of these organelles further revealed that the mitochondria of these multidrug-resistant cells appeared to be highly stressed. The discovery of this mitochondrial stress would be the key to identifying strategies to overcome drug resistance in cells with FBXW7 mutations. Mitochondria are the remains of ancient bacteria that fused with primitive eukaryotic cells billions of years ago. So the scientists thought: If antibiotics attack bacteria, could an antibiotic kill a cancer cell that is too rich in mitochondria? Indeed, anticancer properties of some antibiotics have been identified in the past, but these were isolated cases and therefore potentially attributable to unknown individual mutations in patients. Indeed, the Spanish research team tried it and showed that the antibiotic tigecycline is indeed toxic to FBXW7-deficient cells, opening up a new avenue of research to address multi-resistance. But probably even more important is the discovery of why this antibiotic has anticancer properties.
Tigecycline is a derivative of tetracycline, the first evidence of which on possible anti-cancer effects dates back to the 1970s. It can interact with at least 5-6 human proteins or enzymes, which explains the severity of certain side effects that can arise with the prolonged use of this class of antibiotics. The authors of the research show that tigecycline kills cells by hyper-activating the integrated stress response (ISR) via the GCN2 enzyme and also show that other drugs capable of activating ISR are also toxic to cells with borne mutations. by FBXW7. It is worth noting that many of these ISR-activating drugs are cancer therapies in common clinical use today and were previously assumed to work with other mechanisms. These include halofuginone, gemcitabine for the treatment of carcinomas and leukemia, proteasome inhibitors such as bortezomib used against multiple myeloma, imatinib and derivatives used against leukemia; and the inhibitors erlotinib and sunitinib, members of the protein kinase inhibitors in the targeted-therapy.
Other drugs in clinical experimental phase 2-3 against cancer also act by activating ISR: among them lexibulin (phase 1), the compound ONC201 (phase II) and the glutamine synthase inhibitor CB-839, in phase II for haematological neoplasms and solid tumors. However, the present study reveals that part of the anticancer efficacy of all these chemotherapy drugs is due to their effect in activating ISR, apart from having their own molecular target. This could revolutionize the arsenal of known chemotherapeutic agents, selecting those that also induce ISR to address them to the treatment of cancers where it is more easily activated.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Sanchez-Burgos L et al. EMBO Mol Med. 2022 Jul 21:e15855.
Shen W, Zhou Q et al. Front Oncol. 2022 Apr 19; 12:880077.
Li Y, Wang C et al. Acta Pharm Sin B. 2021; 11(11):3567-3584.
Cui D, Xiong X, Shu J et al. Cell Rep. 2020 Jan; 30(2):497-509.
Dott. Gianfrancesco Cormaci
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