Capire e superare la resistenza innata e acquisita all'inibizione MAPK nell'epatocarcinoma anaplastico.

Anaplastic thyroid cancer (ATC) is highly lethal. Although patients with the BRAFV600E alteration respond to the type I RAF inhibitor (RAFi) dabrafenib with trametinib, most rapidly develop adaptive or acquired resistance. Here, multi-region whole-genome, high-coverage whole-exome, and single-nuclei RNA sequencing of tumors from ATC patients undergoing type I RAFi and MEKi therapy reveals that reactivation of the mitogen-activated protein kinase (MAPK) pathway, along with immunosuppressive macrophage proliferation, may underlie the development of acquired resistance. Screening of several RAFi reveals that ATC cell lines are exquisitely sensitive to the type II RAFi naporafenib, which inhibit