Pazopanib and Paclitaxel Synergize in Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is among the most lethal human cancers, with a median survival of only 5 months. The kinase inhibitor pazopanib has shown single-agent activity in approximately 50% of patients with differentiated thyroid cancer (DTC), which led to its evaluation in ATC. However, although pazopanib monotherapy inhibited ATC cell growth in vitro, it failed to elicit any clinical responses in patients with ATC, prompting Isham and colleagues to investigate whether combination drug strategies could improve pazopanib efficacy in ATC. Combined use of pazopanib with the mitotic inhibitor paclitaxel, known to have single-agent efficacy in ATC but not in DTC, synergized to inhibit colony formation of all ATC cell lines tested. Adding pazopanib to paclitaxel significantly increased cell death in association with heightened mitotic catastrophe compared with paclitaxel treatment alone. Analysis of cell-cycle regulatory kinases revealed that pazopanib potently inhibited Aurora kinase A and B activity both in cell-free extracts and in ATC cells, but only Aurora kinase A was found to be specifically overexpressed in ATC patient samples compared with normal thyroid tissue, suggesting that it may be a therapeutic target in ATC and that its inhibition by pazopanib may underlie synergy between pazopanib and paclitaxel in ATC cells. Indeed, knockdown or small-molecule inhibition of Aurora kinase A synergized with paclitaxel to kill ATC cells, and Aurora kinase A knockdown blunted the synergy between pazopanib and paclitaxel. In a pilot study, the combination of pazopanib and paclitaxel also led to a durable response in an ATC patient, underscoring the clinical relevance of these observations, although a comparison of combination therapy with paclitaxel monotherapy is needed. Based on these findings, specific Aurora kinase A inhibitors may also be effective in ATC, particularly in combination with antimicrotubule agents.

Isham CR, Bossou AR, Negron V, Fisher KE, Kumar R, Marlow L, et al. Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer. Sci Transl Med 2012;5:166ra3.

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