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Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

Abstract: Background: RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo. Methods: We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC. Results: DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions. Conclusions: Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.

 Fuente: Cellular and Molecular Life Sciences: CMLS, 2022, 79, 504

 Editorial: Springer

 Fecha de publicación: 03/09/2022

 Nº de páginas: 19

 Tipo de publicación: Artículo de Revista

 DOI: 10.1007/s00018-022-04530-9

 ISSN: 1420-682X,1420-9071

 Proyecto español: SAF2016-75531-R (MINECO/FEDER, UE)

 Url de la publicación: https://doi.org/10.1007/s00018-022-04530-9

Autoría

ZABALLOS, MIGUEL A.

ACUÑA-RUIZ, ADRIÁN

RIESCO-EIZAGUIRRE, GARCILASO

SANTISTEBAN, PILAR