Abstract 5636: Targeting of NOXA overexpression in anaplastic thyroid cancer (ATC)

Abstract

Abstract Anaplastic thyroid cancer (ATC) is a rare, aggressive and fatal cancer with a median survival of 3-5 months after diagnosis. Our long-term goal is to develop better therapies based on the biology of ATC that contributes to improved tumor response and a reduced risk of potential side-effects. We recently showed that the anti-apoptotic BCL2 family member MCL1 is overexpressed in a subset of ATC and that targeting of MCL1 with quinacrine leads to increased sensitization to the BRAF inhibitor sorafenib. To further investigate the importance of BCL2 family proteins in ATC, we analyzed gene expression data from several published independent gene expression studies. We discovered that both papillary thyroid cancer (PTC) and ATC surprisingly overexpress the mRNA of the pro-apoptotic BCL2 family member NOXA. However, despite the observed overexpression of NOXA mRNA in several ATC cell lines, we find that NOXA protein expression, by contrast, is low. NOXA protein has previously been shown to be subject to ubiquitination and proteasomal degradation. Indeed, through bioinformatics, we find overexpression of several ubiquitin enzymes in ATC suggesting that the half-life of NOXA protein may be selectively reduced in this tumor type. We are further assessing differences in the turnover of NOXA protein in ATC cells and are investigating if restoring NOXA protein expression may synergize with the pharmacologic targeting of MCL1 and other anti-apoptotic BCL2 family members. Interestingly, through TCGA analysis, we discovered that BCL2 overexpression is associated with a poor prognosis in thyroid cancer (THCA) patients. Indeed, treatment with the BCL2/BCLXL inhibitor navitoclax showed encouraging efficacy and synergized with the neddylation inhibitor MLN4924 in the ATC cell line 8505C. This was based on the expectation that MLN4924 would rescue NOXA protein expression. We are pursuing mechanistic studies in a larger panel of thyroid cancer cell lines and in vivo efficacy and toxicity studies. We conclude that restoring NOXA protein expression can together with the rational targeting of anti-apoptotic BCL2 family members may allow for the expansion of the limited ATC-selective treatment strategies currently available. Citation Format: Niklas K. Finnberg, Junaid Abdulghani, Hormoz Ehya, Wafik El-Deiry. Targeting of NOXA overexpression in anaplastic thyroid cancer (ATC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5636. doi:10.1158/1538-7445.AM2017-5636