Browsing by Author "Zaballos, Miguel A."
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Item Inhibiting ERK dimerization ameliorates BRAF‑driven anaplastic thyroid cancer.(Cellular and Molecular Life Sciences, 2022) Zaballos, Miguel A.; Acuña‑Ruiz, Adrián; Morante, Marta; Riesco Eizaguirre, Garcilaso; Crespo, Piero; Santisteban, PilarBackground RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic beneft in several human carcinomas. Here we analyzed the efects of DEL-22379, a relatively specifc 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-specifc characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efcacy in an orthotopic mouse model of ATC. Results DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasisrelated 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 fndings establish that BRAF- and RAS-mutant thyroid cells respond diferentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated signifcant anti-tumor efects 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 diferences elicited by the specifc driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.