Abstract 734: Synergistic antitumor effect of vemurafenib and metformin in thyroid cancer

Abstract

Abstract Advanced thyroid cancer patients such as those with radioiodine-refractory and metastatic differentiated thyroid cancer or anaplastic thyroid cancer lack effective treatment options. Targeted BRAF kinase inhibitors such as vemurafenib have shown promising results in clinical trials and off-label use for patients with BRAFV600E-positive tumors. While targeting BRAFV600E offers particular effectiveness and selectivity in inhibiting cancer cells in the short term, resistance does develop. Prior results in our laboratory confirmed that vemurafenib halts DNA synthesis and induces apoptosis in our mutated thyroid cancer cells. In addition, resistant BCPAP (papillary thyroid cancer) cells were developed in our laboratory by exposing cells to increasing concentrations of vemurafenib. Resistant cells were characterized by hyperactive mitogen-activated protein kinase (MAPK) signaling and resistance to mammalian target of rapamycin (mTOR) inhibition. These additional targets mediating resistance provide an opportunity to devise novel synergistic combination therapies. Since antitumor effects of the widely used antidiabetic agent metformin were observed in thyroid cancer cells and the drug is thought to suppress mTOR, we investigated metformin adjuvant therapy in combination with vemurafenib. Various cell lines including Nthy-ori 3-1 (normal immortalized thyroid cells), BCPAP (papillary thyroid cancer), vemurafenib-resistant BCPAP, and 8505c (anaplastic thyroid cancer) were analyzed in terms of cellular viability, apoptosis and expression of cell signaling molecules after exposure to both drugs. We found that the combination of vemurafenib and metformin caused significantly decreased viability in vemurafenib-resistant BCPAP cells. Furthermore, synergistic apoptosis was observed in BCPAP papillary thyroid cancer cells and 8505c anaplastic thyroid cancer cells in response to the combination treatment. These effects appeared to be mediated by inhibition of both mTOR and MAPK signaling. Results support further investigation into the use of metformin in combination with targeted kinase inhibitors to treat advanced thyroid cancer patients. Citation Format: Elyse K. Hanly, Neha Y. Tuli, Robert B. Bednarczyk, Augustine L. Moscatello, Zbigniew Darzynkiewicz, Jan Geliebter, Raj K. Tiwari. Synergistic antitumor effect of vemurafenib and metformin in thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 734. doi:10.1158/1538-7445.AM2015-734