A team of researchers led by Dr. Javier A. Menendez and Dr. Elisabet Cuyàs from the ProCURE ICO-Girona/IDIBGI program in Girona has identified a strategy that allows predicting and improving the efficacy of "one-two" therapies, a new therapeutic strategy that combines drugs to induce senescence in tumor cells and then specifically eliminate them with senolytic agents.
The findings, published in the Nature group journal Cell Death Discovery, represent a significant advance in precision oncology, as they could enable the design of more personalized and effective treatments and optimize the use of existing drugs. The study was carried out by a multidisciplinary team of scientists from the Catalan Institute of Oncology (ICO) and the Institute of Biomedical Research of Girona (IDIBGI), in collaboration with other national and international research centers.
The "one-two" strategy exploits the Achilles' heel of senescent tumor cells
One-two" therapies, so called because they resemble the most common combination of punches in boxing, have emerged in recent years as a promising approach to improve the efficacy and reduce the toxicity of combined cancer treatments. This concept, originally proposed by Dr. René Bernards (Netherlands National Cancer Institute), is based on a sequential combination of drugs. First, agents are administered that induce cell senescence –a state in which tumor cells stop dividing but do not die (the first strike)– and then, in a second phase, senolytics are administered, compounds or drugs designed to selectively eliminate these "half-knocked-out" or "zombie" cells (the second strike).
This approach has shown great potential in preclinical models to combat resistance to treatment, a recurring problem in oncology. In many cancers, tumor cells that survive chemotherapy or radiation therapy can enter a state of senescence and reactivate over time, contributing to tumor progression and metastasis. The sequential combination of a senescent agent with a senolytic drug aims to avoid this problem by eliminating the cells before they can regain their proliferative capacity. In addition, because the first and second "punch" drugs are administered separately, the possibility of toxicities that typically limit the use of concurrently combined therapies is minimized.
One of the major challenges in developing these "one-two" strategies has been the lack of tools to predict which tumors will respond best to this approach. Until now, there has been no way to determine the sensitivity of senescent tumor cells to senolytic agents, making their clinical application difficult.
The role of mitochondrial preconditioning in the response to senolytics
The study, published in Cell Death Discovery, has shown that the key to predicting the effectiveness of senolytics lies in what is known as "mitochondrial preconditioning" – that is, the state of readiness of the mitochondria of tumor cells to initiate the process of apoptosis, or programmed cell death.
The researchers used a technique called "BH3 profiling", a method that allows them to evaluate the state of mitochondria in terms of their proximity to the threshold of cell death. By analyzing different types of tumor cells induced to senesce by different therapeutic agents, the team discovered that not all senescent cells have the same predisposition to apoptosis.
"It was thought that senescent tumor cells were universally vulnerable to senolytic agents because they were able to survive very close to their cell death threshold, but our results show that, on the contrary, they move away from this threshold by activating specific resistance mechanisms", explains Javier A. Menendez, a senior author of the study. "The key is a member of the BCL-2 family, specifically the protein BCL-xL, which acts as a common protective factor in many, if not all, types of senescent cells". The researchers demonstrated that regardless of the therapeutic agent used to induce senescence, the tumor type and the genetic characteristics of the tumor, senescent cells share a common dependence on BCL-xL to avoid death. This suggests that specific inhibitors of this anti-apoptotic protein, such as the experimental drug A1331852, could be used as an effective senolytic strategy in multiple cancer types.
A new horizon for more precise and effective therapies
This finding could redefine the way "one-two" anti-cancer strategies are designed, as it allows the prior identification of which tumors and which patients could benefit most from a senogenic-senolytic strategy.
"Our results suggest that the mitochondrial profile of a tumor cell could be used as a functional biomarker to select the best treatment", says Elisabet Cuyàs, co-leader of the study. "This would help optimize the combination of drugs and reduce side effects, avoiding the administration of certain senolytics to patients who would not benefit from them".
In addition to its implications for oncology, the study opens up new opportunities in other areas of biomedicine. Senescent cells are involved in many age-related diseases, such as pulmonary fibrosis, arthritis and cardiovascular disease. The development of more specific senolytics could have applications beyond cancer in the treatment of diseases associated with the accumulation of senescent cells in damaged tissues.
The researchers emphasize that although the study was conducted in cell and preclinical models, these findings provide a solid basis for the development of clinical trials in patients. In particular, they suggest that BCL-xL inhibitors could be tested in combination with already approved senescent therapies, such as palbociclib, olaparib or doxorubicin, to improve their efficacy.
Next steps: towards personalized clinical trials
The next step will be to validate these findings in clinical trials analyzing the efficacy of combining senolytic therapies with BCL-xL inhibitors in different types of cancer.
"We hope that in the coming years we will be able to design more personalized treatments, in which mitochondrial profiles will be carried out before administering a senolytic" conclude Àngela Llop, Dr. Sara Verdura and Júlia López, co-first authors of the paper. "This would not only improve the efficacy of therapies, but also reduce side effects by avoiding the simultaneous combination of unnecessary drugs in patients who would not obtain any clinical benefit". The study represents an important advance in predicting the efficacy of "one-two" therapies in oncology and underscores the importance of understanding the molecular biology of cellular aging in order to develop new therapeutic strategies. By identifying BCL-xL as a universal target in senescent tumor cells, the researchers have taken another step toward precision oncology, where each treatment can be tailored to the mitochondrial profile of each tumor.
Reference article: López, J., Llop-Hernández, À., Verdura, S. et al. Mitochondrial priming and response to BH3 mimetics in “one-two punch” senogenic-senolytic strategies. Cell Death Discov. 11, 91 (2025). https://doi.org/10.1038/s41420-025-02379-y
