Investigation of Novel Pan-RAF Inhibitors in Anaplastic Thyroid Cancer

Sarah EB Ryan, Western University

Abstract

Anaplastic Thyroid Cancer (ATC) is rare. Most patients present with extensive disease that is surgically unresectable. Frequently tumours are resistant to chemotherapy and radiation, leaving patients with few treatment options. A subset of ATC patients carry a BRAF^V600E mutation and may be offered a first generation BRAF inhibitor (Dabrafenib). However, only some respond, and all will eventually acquire resistance and progress. A novel class of pan-RAF inhibitors has been developed that may benefit patients with BRAF and other currently unactionable mutations. One such inhibitor, Naporafenib, decreased cell viability in BRAF^MUT and wild-type ATC cell lines greater than Dabrafenib. Naporafenib also decreased immune checkpoint inhibitor molecule PDL1 expression in ATC cells, indicating potential synergy with immunotherapies. Importantly, Naporafenib decreased MAPK signaling in ATC cells, as demonstrated through immunofluorescence-microscopy and RNA sequencing. RNA sequencing also highlighted potential off-target effects of Naporafenib. Our work demonstrates the activity of these pan-RAFi in ATC models.