Anaplastic (ATC) and refractory
papillary thyroid cancer (PTC) lack effective treatments. Inhibition of either oncogenic BRAF or SRC has marked anti-
tumor effects in mouse models of
thyroid cancer, however, neither
drug induces notable apoptosis. Here we report that the SRC-inhibitor
dasatinib further sensitizes BRAFV600E-positive
thyroid cancer cells to the BRAFV600E-inhibitor
PLX4720. Combined treatment with
PLX4720 and
dasatinib synergistically inhibited proliferation and reduced migration in PTC and ATC cells. Whereas
PLX4720 did not induce robust apoptosis in
thyroid cancer cells, combined treatment with
dasatinib induced apoptosis in 4 of 6 lines. In an immunocompetent orthotopic mouse model of ATC, combined
PLX4720 and
dasatinib treatment significantly reduced
tumor volume relative to
PLX4720 treatment alone. Immune cell infiltration was increased by
PLX4720 treatment and this effect was maintained in mice treated with both
PLX4720 and
dasatinib. Further, combined treatment significantly increased
caspase 3 cleavage in vivo relative to control or either treatment alone. In conclusion, combined
PLX4720 and
dasatinib treatment induces apoptosis, increases immune cell infiltration and reduces
tumor volume in a preclinical model of ATC, suggesting that the combination of these FDA-approved drugs may have potential for the treatment of patients with ATC or refractory PTC.