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 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.
Highlights
While traditional treatments of papillary thyroid cancer (PTC), including thyroidectomy, thyroidstimulating hormone (TSH) suppression, and radioactive iodine (RAI) are highly effective at mitigating disease, patients with advanced PTC or undifferentiated thyroid cancer (ATC) face poor prognosis and need novel therapeutics
We have previously shown that BRAFV600E plays an important role in the aggressive behavior of thyroid cancer cells in vitro and that treatment with the selective BRAFV600E-inhibitor PLX4720 results in impressive decreases in tumor volume and metastasis in an orthotopic mouse model of ATC [5,6,7,8, 10]
Treatment of the murine ATC cell lines (TBP3743, TBPt-3403 and TBPt-3610R) with 1 μM of the BRAFV600E-inhibitor PLX4720 decreases pERK(T202/ Y204), a more complete reduction is achieved with a dose of 10 μM
Summary
While traditional treatments of papillary thyroid cancer (PTC), including thyroidectomy, thyroidstimulating hormone (TSH) suppression, and radioactive iodine (RAI) are highly effective at mitigating disease, patients with advanced PTC or undifferentiated (anaplastic) thyroid cancer (ATC) face poor prognosis and need novel therapeutics. We have previously shown that BRAFV600E plays an important role in the aggressive behavior of thyroid cancer cells in vitro and that treatment with the selective BRAFV600E-inhibitor PLX4720 results in impressive decreases in tumor volume and metastasis in an orthotopic mouse model of ATC [5,6,7,8, 10]. These findings, combined with data from others, led to a phase II clinical trial (NCT01286753) to evaluate the selective BRAFV600E-inhibitor vemurafenib in patients with progressive RAI-refractory BRAFV600E-positive PTC. In a separate case, a patient with ATC exhibited a response to treatment with www.impactjournals.com/oncotarget
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