Researchers identify a mechanism involved in the resistance to antitumor treatment

Researchers of the Molecular Pathology group at Vall d’Hebron Research Institute (VHIR), headed by Dr. Santiago Ramon y Cajal, have discovered that the phosphorylation of a protein, elF4E, confers resistance to cell stress, including the treatments that damage DNA, like cisplatin. The results of the study have been published inPLOS ONE.

After a decade studying the signaling factors in in vitro models, researchers observed that high levels of 4EBP1 and EIF4E phosphorylated are associated with more aggressive tumors and a worse prognostic. Seeing these unexpected results, researchers from VHIR decided to start this study to analyze the role of the elF4E phospholylation and its implication in the resistance to agents that produce cell stress, like gene damage.

With the collaboration of Dr Nahum Sonenberg’s group, from the University of McGill in Montreal (Canada), VHIR’s team carried out in vitro and murine models with several molecular approaches. With these models, as Dr Ramon y Cajal said “we have seen that blocking the elF4E phosphorylation, genetically or with chemical inhibitors, we cells become more sensitive to the classic treatment with chemotherapy”.

With these results, the study’s lead author says that the door to optimize the standard chemotherapy treatment has been opened: “if we combine the chemotherapy of cytotoxic agents (like cisplatin) with selective inhibitors of these kinases, that don’t have relevant side effects, patients will suffer fewer side effects”. Additionally, the cytotoxic dose will be reduced and therapeutic effect increased.

At present, there are two types of treatments available to fight against tumor cells: the cytotoxic treatments, which have a powerful antitumor effect but present many side effects, and the treatments with specific inhibitors for punctual genetic alterations, which are very selective and have fewer side effects. Nevertheless, tumor cells have many molecular alterations, and tumors usually become resistant to the specific inhibitors therapy.

Now, together with the Organic Chemistry group from the Instituto Químico de Sarrià, VHIR researchers are trying to find new MNK kinase inhibitors, which would be more selective and effective, in order to potentiate the antitumor effect of the chemotherapy treatment with cytotoxic agents.

Photo: Dr. Marta Sesé and Dr. Santiago Ramón y Cajal