Inhibiting ERK dimerization ameliorates BRAF-driven anaplastic thyroid cancer

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 in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Thus, 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. 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 analyzed 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.