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Abdulghani J, Gokare P, Gallant JN, Dicker DT, Whitcomb T, Cooper TK, Liao J, Derr J, Liu J, Goldenberg D, Finnberg NK, El-Deiry WS
Sorafenib and quinacrine target anti-apoptotic protein Mcl-1: a poor prognostic marker in anaplastic thyroid cancer (ATC)
Clin Cancer Res (2016) 22:6192-6203.
Abstract
PURPOSE: Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFkappaB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug quinacrine known to target NFkappaB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFkappaB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo. RESULTS: We detected increased expression of NFkappaB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFkappaB signaling. CONCLUSION: The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients.
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Publication Date: 2016-12-15.
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Last updated on Wednesday, September 06, 2017