Abstract LB-182: Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer

Abstract

Abstract Anaplastic thyroid cancer (ATC), contrary to well-differentiated papillary thyroid cancer (PTC), is one of the most aggressive human malignancies. Anaplastic thyroid cancer is responsible for more than half of all thyroid cancer deaths, with an overall mortality rate about 70% at 6 months and 81% at 12 months, despite only accounting for <2% of thyroid cancer incidence [1]. Both PTC and ATC are MAPK-driven cancers that have two mutually exclusive drivers with distinct signaling consequences: BRAF V600E mutation and RAS mutation [2-3]. In PTC, BRAF (V600E)-like tumors showed higher MAPK transcriptional output and lower expression of genes related with iodine metabolism, and RAS-like tumors showed lower MAPK signaling and comparatively higher expression of iodine metabolism genes. However, in ATC both BRAF mutant and RAS mutant tumors showed BRAF-like tumor transcriptional output. Down-regulation of Notch signaling by gamma-secretase inhibitor (GSI) or Notch1 RNAi reduced PTC cell proliferation [3]. Here by combining multiple gene expression microarray studies (TCGA, GSE27155, GSE29265 and GSE33630), we showed that compared with normal thyroid tissue the Notch signaling pathway was up-regulated in both PTC and ATC. However, ATC and PTC showed different activation patterns in terms of expression of Notch receptors, ligands and downstream targets. Compared with normal thyroid tissue, Notch1, Notch3 and JAG1 were up-regulated in both ATC and PTC, but were much higher in ATC. Compared with normal thyroid tissue, HEY1, HES4 and NRARP were up-regulated in both ATC and PTC. Comparing with PTC, HEY1 was also higher in ATC. However, HES1 was down-regulated in ATC but up-regulated in PTC. It was also reported that both Notch1 and Hes1 were up-regulated by activation of MAPK signaling in thyroid follicular cells with RET/PTC3 or BRAF (T1799A) [4]. Notch1 protein level was also higher in PTC [3]. All of the evidence above supports the hypothesis that Notch pathway may be a key signaling component along with aberrant activation of MAPK pathway in ATC. These data suggest inhibition of Notch signaling alone and/or combination with MAPK signaling inhibitors, such as BRAF inhibitor or ERK inhibitor, may be of benefit in ATC, and support investigation in a clinical trial. 1. Anaplastic Thyroid Carcinoma: Treatment Outcome and Prognostic Factors. Cancer 103 1330-1335,2015. 2. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 159, 676-690, 2014. 3. Notch Pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Translational oncology, 6,197-205, 2013. 4. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. JCI, 126, 1052-1066, 2016. Citation Format: Yan Ding, Hui-Rong Qian, Bharvin K R Patel, Gerald Joseph Oakley, Karim A. Benhadji, Emma Bowden, Amit Aggarwal. Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-182.