- Guillermo de Cárcer demonstrates that changes in the osmotic stress of tumor cells can generate resistance or sensitivity to anticancer drugs, depending on the nature of the drugs
- The results, published in the scientific journal Drug Resistance Updates, open the door to defining new biomarkers for the use of these drugs
Today, February 4, is World Cancer Day, established in 2000 at the World Summit Against Cancer in Paris. The "Paris Charter," signed on February 4, 2000, set as its objectives promoting cancer research and prevention, improving patient care, raising awareness about the disease, and increasing public consciousness in the fight against cancer. What better way to commemorate this day than with the research results conducted by the Cell Cycle and Cancer Biomarkers group y liderado por Guillermo de Cárcer en el Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM y publicados recientemente.
Comunicación del CSIC published a press release about these results today, February 4, which we are sharing on the IIBM News page.
Guillermo de Cárcer and his research team from the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), a joint center of the Consejo Superior de Investigaciones Científicas (CSIC) and the Universidad Autónoma de Madrid (UAM), have described a new molecular mechanism of resistance to Rigosertib, one of the most promising experimental drugs for inhibiting the growth of cancer cells. The results, published in Drug Resistance Updates, not only show cell growth in the presence of this drug and other analogs but, more revealingly, describe how cancer cells develop greater sensitivity to compounds that use molecular mechanisms opposite to those of Rigosertib, which could significantly impact chemotherapy response.
One of the major challenges in cancer therapies is the emergence of resistance mechanisms in tumors after chemotherapy treatment. A tumor is a very heterogeneous entity that contains cells with thousands of genetic combinations that grant plasticity and the ability to adapt to any external stress. This plasticity is key to enabling tumor cells to find escape routes from anticancer therapies, developing resistance mechanisms that lead to tumor recurrence after treatment. Once they reappear, therapies are no longer effective.
Currently, this is a very active area of research, with many scientific groups trying to define the molecular mechanisms behind this therapy resistance in order to identify biomarkers that help determine which therapeutic strategy is most appropriate for each patient and to seek alternatives once resistance appears.
With a similar goal, the research group led by Guillermo de Cárcer conducted a genetic screening to identify the mechanisms of resistance to Rigosertib. Despite being initially promising, this drug has not yet been used clinically because the type of tumor most suitable for its use is not well understood, partly due to its multiple mechanisms of action.
Resistance or Sensitivity Depending on the Drug
The research results define a new molecular mechanism of resistance to Rigosertib, supported by the activity of the WNK1 protein, which is a master sensor of osmotic stress. When WNK1 is inactivated, the cells become refractory to treatment with Rigosertib, and they can grow indefinitely in the presence of the drug.
What is most striking about this result is that the inactivation of WNK1 not only confers resistance to Rigosertib but also to other drugs that have a similar molecular mechanism, which aims to destroy the internal scaffold of cells by dismantling microtubule fibers. Ana Monfort, the first author of the article and a researcher at IIBM, still remembers the surprise of the result when testing other drugs: "When we tested other drugs with a mechanism of action similar to Rigosertib and saw that there was also resistance, we understood we had something truly important on our hands."
Even more remarkable is the result obtained when the researchers tested drugs with a molecular mechanism opposite to that of Rigosertib—those that stabilize the cellular scaffold, such as Paclitaxel or Epotilone. "We then saw the complete opposite effect, that cells with inactive WNK1 become more sensitive to these compounds, and we can reduce the dose while achieving the same lethality," says Natalia Sanz, a researcher in the group and co-author of the article.
Osmotic Stress Modifies Chemotherapy Response
WNK1 is a master modulator of osmotic balance inside cells. Its function is to open and/or close the channels that allow ions to pass into the cell, adapting the cell to changes in external ionic concentration.
For this reason, the researchers conducted a very simple and revealing experiment. When tumor cells were incubated in a hypotonic medium (low ion concentration), the cells became sensitive to Rigosertib but resistant to Paclitaxel and Epotilone. However, when they incubated the cells in a hypertonic medium (high ion concentration), the effect was completely reversed. "This demonstrates that inducing osmotic stress in tumor cells can have a significant modulatory effect on the response to anticancer drugs," says the study's director, Guillermo de Cárcer.
Although still preliminary, this work has very relevant clinical implications. Many cancer patients, during chemotherapy treatment, are also medicated with diuretics, as chemotherapy often induces side effects like hypertension, fluid retention, etc. The study's director reflects on these data: "Diuretics are drugs that basically modify the osmotic balance of cells. Our results indicate that they could have a direct impact on the response to chemotherapy, and this is something we are going to explore in the lab's upcoming projects."
This research was conducted in collaboration with the Centro Alemán de Investigación del Cáncer (DKFZ-Heidelberg), the Instituto de Investigación del Hospital 12 de Octubre (i+12) and the Universidad de Castilla la Mancha (UCLM); and funded by the Asociación Española Contra el Cáncer, la Agencia Estatal de Investigación, and the CSIC itself. Guillermo de Cárcer is a member of the Conexión Cáncer-CSIC group and also part of the “Investigación Traslacional en Cáncer” group at the Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS.
The image shows a colony of breast cancer cells resistant to Rigosertib, surrounded by cells that have halted their proliferation thanks to the drug.
Ana Monfort-Vengut, Natalia Sanz-Gómez, et al,. Osmotic stress influences microtubule drug response via WNK1 kinase signaling. Drug Resistance Updates, 2025. https://doi.org/10.1016/j.drup.2025.101203