A new experimental strategy enables the elimination of proteins involved in pathological processes

A preclinical study carried out by the Institute of Advanced Chemistry of Catalonia (IQAC) and the Institute for Molecular Biology of Barcelona (IBMB), both part of the Spanish National Research Council (CSIC), has developed a strategy that enables the forced elimination of proteins that help tumors survive chemotherapy. This finding opens a new avenue to tackle resistance to cancer treatments, one of the major challenges in oncology. The research, published in Nature Communications, provides a proof of concept for a new mechanism of induced degradation of harmful proteins, expanding the potential for developing more effective therapies in the future.

“Our study presents an optimized experimental methodology, as an alternative to the conventional pathway of induced degradation. This approach could allow the design of more precise treatments for diseases such as cancer, as well as overcome or even reverse chemoresistance in certain cases,” explains Bernat Crosas, CSIC researcher at IBMB, who led the study together with Gemma Fabriàs, researcher at IQAC-CSIC and CIBEREHD, and Jordi Bujons, from IQAC-CSIC. Researchers from the University of Barcelona also participated in the study.

Protein recycling system

Our cells have a sophisticated machinery responsible for removing defective or unnecessary proteins: the ubiquitin–proteasome system, which acts as a recycling pathway for protein material. In this process, proteins that need to be destroyed are “tagged” with a molecule called ubiquitin, allowing them to be recognized and degraded by the proteasome, an organelle present in all cells.

In recent years, new—still experimental—tools have been developed to eliminate harmful proteins from the body by targeting the proteasome. One such approach involves the so-called PROTACs (Proteolysis Targeting Chimeras), molecules designed to trigger the tagging of target proteins with ubiquitin and induce their destruction. However, this approach has limitations, as it depends on highly specific cellular mechanisms that do not always function properly.

“The conventional process works like a waste collection system: first, ‘waste’ is tagged with ubiquitin units and then transported to the recycling plant, the proteasome,” explains Mireia Casasampere, IQAC-CSIC researcher and first author of the study. “However, this system can sometimes be inefficient because it relies on several intermediate steps between protein tagging and its elimination,” she adds.

A shortcut to process cellular “waste”

This research explores an alternative strategy based on bypassing the tagging step and delivering proteins directly to the proteasome. “In this case, we take the proteins straight to the cell’s recycling system,” explains Tania Roda, also a researcher at IQAC-CSIC.

The team has designed and synthesized new PROTAC-like molecules capable of directing two proteins relevant in cancer to the proteasome without requiring the intermediate ubiquitination step: IMPDH2, a key enzyme in cell replication and therefore linked to tumor growth, and CERT1, a lipid transporter protein involved in processes related to tumor cell death. These designed PROTAC molecules are modular: one part recognizes the protein to be eliminated (IMPDH2 or CERT1), while the other binds to a proteasome-associated component (USP14) that regulates its activity.

As Gemma Fabriàs explains, “these are high-affinity molecules that bind to the target protein and deliver it to the precise location where it will be degraded and destroyed.” This represents a simpler and more efficient mechanism of action. The outcome is the inactivation of the tumor cell, which can no longer replicate, or its death by apoptosis.

Targeted degradation

Tests carried out in cancer cells have demonstrated the effectiveness and potential of this new targeted degradation strategy, avoiding some of the limitations of existing technologies, which depend on specific cellular mechanisms that may not function properly in certain pathological contexts.

Moreover, the results suggest that by eliminating CERT1, tumor cells can regain sensitivity to some chemotherapy treatments. “If CERT1 is blocked in certain carcinomas, chemotherapy may become effective again. Although our results are still very preliminary, they open a possible path for tumors to respond again to treatments, reducing resistance—a very common problem in cancer. In fact, in some cancer types, between 60% and 90% of patients may develop resistance to chemotherapy, a situation that can worsen in metastatic cases,” concludes Bernat Crosas.

The team is currently focused on optimizing these molecules to improve their efficacy and specificity, as well as exploring their application in more advanced models with a view to potential clinical use.

Although still at an early stage, this approach is highly promising and expands the available tools for targeted protein degradation. It could contribute to the development of future, more precise therapies against complex diseases such as cancer, as well as other conditions in which a specific target protein has been identified.

This research was funded by the Spanish Ministry of Science, Innovation and Universities and by the European Union’s Next Generation funds, through the CSIC Global Health Platform (PTI Salud Global) and the Government of Catalonia.

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