Combined BRAFV600E- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer

// Pierre Vanden Borre 1 , Viswanath Gunda 1 , David G. McFadden 2 , Peter M. Sadow 1 , Shohreh Varmeh 1 , Maria Bernasconi 1 and Sareh Parangi 1 1 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 2 Thyroid Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts Correspondence: Sareh Parangi, email: // Keywords : Thyroid, BRAF, SRC Received : April 3, 2014 Accepted : June 24, 2014 Published : June 26, 2014 Abstract 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 BRAF V600E -positive thyroid cancer cells to the BRAF V600E -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.