Scientists from the Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, in collaboration with scientists from IBBTEC (CSIC-UC), have analyzed the antitumor effects of an ERK dimerization inhibitor for the treatment of anaplastic thyroid carcinomas.
The results, published in Cellular and Molecular Life Sciences, highlight the differential response of tumors with different oncogenic burden to targeted therapies.
In general, thyroid cancer has a very good prognosis, due to the efficacy of standard treatment, which consists of surgical removal of the gland and subsequent treatment with radioactive iodine. Unfortunately, a number of these carcinomas progress to very aggressive forms, which lose their differentiated state. Among these are anaplastic thyroid carcinomas, one of the most lethal human cancers, which currently have no effective treatment. Since these tumors are enriched in mutations in the RAS-ERK signaling pathway, therapies using specific kinase inhibitors are being investigated. However, the emergence of resistance to these drugs and thus tumor recurrence is very frequent. Dr. Miguel Angel Zaballos Sánchez and Dr. Adrián Acuña Ruiz, first authors of the work of Dr. Pilar Santisteban's group (Department of Cancer Biology at IIBM), in collaboration with researchers from IBBTEC (CSIC-UC), have proposed an alternative strategy based on the inhibition of ERK dimerization.
In the work recently published in the journal Cellular and Molecular Life Sciences, the authors explored a therapeutic option based on blocking protein interactions by using the molecule DEL-22379, which is an inhibitor of ERK dimerization, instead of focusing on inhibiting the kinase activity of the components of the RAS-ERK pathway. The results showed that the new therapeutic approach had potent antitumor effects, both in vitro and in vivo, on BRAF-mutated thyroid tumor cells. However, these effects were less clear in cells with RAS mutations.
Fortunately, the authors were able to verify that the mice treated with this ERK dimerization inhibitor did not show any signs of toxicity, which is very frequent when other kinase inhibitors are used, which allowed them to propose this inhibitor, the molecule DEL-22379, as a possible new therapy for the treatment of anaplastic thyroid carcinomas, in combination with other inhibitors.
Dr. Miguel Angel Zaballos Sánchez, postdoctoral researcher at the IIBM and Dr. Adrián Acuña Ruiz, postdoctoral researcher, currently at the Sloan Kettering Institute, are first authors of this work, performed under the supervision of Dr. Pilar Santisteban.
Dr. Garcilaso Riesco Eizaguirre, from Hospital Universitario de Móstoles and Drs. Marta Morante and Piero Crespo, from IBBTEC, also participated in this work, which was funded by AECC-GCB141423113.
The photograph shows an immunofluorescence image of the cytoskeleton architecture of thyroid tumor cells in response to ERK inhibition.