Researchers from the Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, in collaboration with researchers from the IBBTEC (CSIC-UC), have analyzed the antitumor actions of an inhibitor of ERK dimerization for the treatment of the aggressive anaplastic thyroid carcinoma. The results, published in Cellular and Molecular Life Sciences, underscore the different response to therapeutic agents of tumors carrying different oncogenes.
Researchers at the IIBM (CSIC-UAM), in collaboration with the IBBTEC (CSIC-UC), have analyzed the actions of a molecule that impairs ERK dimerization for the treatment of anaplastic thyroid carcinomas, one of the deadliest human carcinomas. Given that these carcinomas are currently untreatable, and do not respond well to the treatment with small kinase inhibitors, in this work, we proposed an alternative treatment based in the impairment of ERK dimerization.
In general terms, thyroid carcinomas present an excellent prognosis, with a highly effective therapeutic strategy based on thyroid ablation and treatment with radioiodine. Unfortunately, a subset of those indolent carcinomas progress to undifferentiated and very aggressive forms of the disease, in especial the Anaplastic Thyroid Carcinoma, that do not respond to the conventional treatment. For those carcinomas, enriched in mutations in the RAS to ERK signaling pathway, therapies based in small kinase inhibitors are under intensive evaluation, however emergence of resistance to these drugs and relapse of the tumor is common in these patients.
In this work, rather than focusing on the inhibition of the kinase activity of the pathway, the authors explored a therapeutic option based on the impairment of protein-protein interactions, using the molecule DEL-22379, a relatively specific inhibitor of ERK dimerization, the final effector of the RAS to ERK pathway.
This therapeutic approach had significant in vitro and in vivo antitumor effects on thyroid tumor cells with BRAF mutations, however those effects were very mild on thyroid tumor cells with RAS mutations. Furthermore, the mechanism of action of the drug was different in thyroid tumor cells than the one previously described for other tumor types, affecting to the activation of kinases upstream from ERK.
In addition, the treatment of mice with this drug did not result in adverse effects, that are commonly associated to inhibitors of this pathway, proposing this drug as a good treatment option to be used in combinatorial treatments.
Dr. Miguel Angel Zaballos Sánchez, postdoctoral researcher at the IIBM, and Dr. Adrián Acuña Ruiz, postdoctoral researcher, currently at Sloan Kettering Institute, are the first co-authors of this work, that was carried out under the supervision of Dr. Pilar Santisteban, CSIC Full Professor at the IIBM. Dr. Garcilaso Riesco Eizaguirre, from Hospital Universitario de Móstoles and Dr. Marta Morante and Dr. Piero Crespo, from IBBTEC, also participated in this work, that was funded by grant AECC-GCB141423113.
Zaballos MA, Acuña-Ruiz A, Morante M, Riesco-Eizaguirre G, Crespo P, Santisteban P. Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer. Cell Mol Life Sci. 2022 Sep 3;79(9):504. doi: 10.1007/s00018-022-04530-9. PMID: 36056964; PMCID: PMC9440884.
Immunofluorescence image showing cytoskeletal architecture of thyroid tumor cells after ERK inhibition.