Abstract

PURPOSE: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment result in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than single agent or BRAF and MEK inhibitors.EXPERIMENTAL DESIGN: The combined drug activity was analyzed to predict any synergistic effect using high throughput screening (HTS) of active drugs. We performed follow up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs.RESULTS: The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720 resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (p < 0.05), lower number of metastases (p < 0.05) and longer survival (p < 0.05) compared to monotherapy and vehicle control.CONCLUSIONS: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

View details for DOI 10.1158/1078-0432.CCR-19-1606

View details for PubMedID 31937621