Abstract 1895: The role of the IFNγ pathway in the development of vemurafenib resistance in BRAF^V600Emutant thyroid carcinoma

BRAFV600E is the most common driver mutation in anaplastic thyroid cancer, and BRAF inhibitors are increasingly being used in the treatment of this disease. However, the therapeutic benefit of BRAFV600E inhibitors, such as vemurafenib, has been limited in thyroid cancer due to rapid development of drug resistance in clinical practice. Here, we characterize a targetable mechanism of vemurafenib resistance by studying vemurafenib-resistant clones derived from BRAFV600E mutant anaplastic thyroid cancer cell lines (8505C and FRO), and propose a drug combination to overcome resistance. Vemurafenib resistance in these established clones was verified by persistent activation of ERK1/2 after vemurafenib treatment by western blot analysis. RNA-sequencing and subsequent ingenuity pathway analysis (IPA) was used to identify differences in pathway activation after vemurafenib treatment in parental and vemurafenib-resistant cell lines. Treatment of parental cells with vemurafenib resulted in differential gene expression correlating with upstream activation of the IFNγ-STAT1-IRF1 pathway (All FDR Citation Format: Jessica Limberg, Katherine D. Gray, Mandeep Singh, Timothy M. Ullmann, Brian Wyrwas, Weibin Wang, Zachary Lowenstein, Steve El Eshaky, Heng Liang, Wei Li, Tuo Zhang, Jenny Xiang, Dessislava Stefanova, Rasa Zarnegar, Thomas J. Fahey, Irene M. Min. The role of the IFNγ pathway in the development of vemurafenib resistance in BRAFV600E mutant thyroid carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1895.