Abstract 2426: JAK inhibitors as new drugs for treatment of paclitaxel-resistant anaplastic thyroid cancer

Abstract

Abstract Background: Anaplastic thyroid carcinoma (ATC) is a rare but particularly aggressive solid tumor that has a poor prognosis, despite multimodal treatment approaches. New chemotherapy agents are being developed and taxanes have efficacy against ATC. Targeted agents including fosbretabulin, imatinib, erlotinib and gefitinib have also been examined, but were unsuccessful. These results suggest that innovative strategies are required for treatment of ATC. Therefore, our primary aim was to determine the genes and pathways related to sensitivity to paclitaxel as biomarkers in ATC. Our secondary aim was to identify new genes and pathways as therapeutic targets in ATC. Materials and Methods: We analyzed differences in gene expression profiles before and after treatment with paclitaxel in two ATC cell lines: KTA-3 cells, which are sensitive to paclitaxel, and TTA-2 cells, which are resistant to paclitaxel. Parametric Analysis of Gene Set Enrichment (PAGE) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Transcriptional Regulatory Element Database (TRED) were performed to detect significant differences at the level of functional categories such as pathway genes and transcriptionally regulated genes. Results: Genes in the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway (KEGG classification) were downregulated significantly in KTA-3 cells compared with TTA-2 cells after treatment with paclitaxel. PAGE showed that breast cancer susceptibility gene (BRCA)1-related genes including Janus kinase (JAK)1, JAK2 and signal transducer and activator of transcription (STAT)3 were downregulated most significantly in KTA-3 cells compared with TTA-2 cells after paclitaxel treatment. Several JAK inhibitors inhibited cell growth in paclitaxel-resistant ATC cells. Conclusions: JAK-STAT pathway may be a biomarker of paclitaxel sensitivity in ATC and may represent a new target in drug development for ATC therapy. Citation Format: Tomoyuki Fujita, Takayuki Sasaki, Zheng Wang, Kayoko Koshikawa, Hajime Nishimura, Minoru Fujimori. JAK inhibitors as new drugs for treatment of paclitaxel-resistant anaplastic 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 2426. doi:10.1158/1538-7445.AM2015-2426