New avenue against chemotherapy-resistant tumors

A team from the Valencia Institute of Biomedicine (CSIC) and the Príncipe Felipe Research Center finds a mechanism that cells use to evade chemotherapy. The work opens the door to incorporating drug combinations to inhibit chemoresistance.

Image of a skin cancer where the expression of the glucose transporter (Glut1) is seen in green, the protein pyruvate kinase 2 (PKM2) is seen in red, and DNA is seen in blue. / IBV-CIPF

A study led by the Joint Research Unit of the Valencia Biomedicine Institute (IBV-CSIC), the Higher Council for Scientific Research (CSIC) and the Príncipe Felipe Research Center (CIPF), discovers a mechanism by which cells evade chemotherapyy, not only do they survive it, but they become more aggressive.

Key to the process is protein synthesis that allows cells to adapt to the stress caused by chemotherapy. By better understanding the mechanism and characteristics of the cells that survive, we could intervene in the process by combining existing drugs, improving the effectiveness of the treatments. The work is published in the journal Signal Transduction and Targeted Therapy.

It is essential to deepen our knowledge of the mechanisms of resistance to antitumor therapies in order to improve the effectiveness of treatments. The group led by Francisco José Iborra in the Joint Research Unit of the IBV-CSIC and the CIPF studies these mechanisms of resistance to oncological therapies using cell lines derived from human tumors, which they undergo treatment and where they study the changes that have occurred in the resistant cells.

Thus, “in this study we have found that a mechanism that cells use to evade chemotherapy is a consequence of the stress response induced by chemotherapy,” explains Iborra. This response triggers protein degradation, which causes the concentration of its basic components (amino acids) to increase within the cell, inducing, in turn, protein synthesis.

As a final result, the cell reduces its size and increases protein turnover. “This last point is very important, since a high protein turnover is necessary for cellular plasticity, since cells must respond by changing their phenotype,” says the researcher.

Increase the effectiveness of chemotherapy

This study represents an important step, since it opens the possibility of designing more targeted and effective combined therapies for the treatment of cancer and, therefore, improving current treatments, increasing survival and the quality of life of patients. “We will be able to design therapies with protein synthesis inhibitors, or proteasome or autophagy inhibitors, which will increase the effectiveness of chemotherapy,” maintains the CSIC researcher.

“In our laboratory we have studied this possibility and we have observed that these combinations exert a positive synergistic effect, which suggests that this strategy could be useful in the treatment of tumors resistant to chemotherapy,” highlights the scientist. “But before moving to the clinical field, we must test these combinations in animal models,” he emphasizes.

This research has been carried out in the CIPF laboratories in Valencia, using tumor cell lines in culture of various types of tumors and computational modeling. The research has been developed with the collaboration of the National Center for Biotechnology (CNB-CSIC), the Hospital del Vinalopó (Elche) and the University of Helsinki (Finland).


Francisco J. Iborra, et al. “Chemotherapy induces cell plasticity; “controlling plasticity increases therapeutic response.” Signal Transduction and Targeted Therapy(2023)