Abstract LB-089: Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells

Abstract

Abstract Despite recent advancements in chemotherapy and radiation, anaplastic thyroid cancer (ATC) remains an almost invariably lethal disease with an average life expectancy of 2-6 months. Current interventions, including surgery are palliative, underlining the urgent need for novel, effective approaches. Targeting the apoptosis pathway using BH3 mimetics is effective in hematologic malignancies. However, in solid tumors, the response to these compounds is usually limited and short-lived. In addition, most ATCs have lost p53, resulting in a significant dampening of the pro-apoptotic signals deriving from chemotherapy or radiation. We hypothesized that a small molecule that directly binds to and activates BAX, bypassing the need for upstream activating signals, might effectively induce apoptosis in ATC cells. We used a novel activator, EGAV1, that is derived from the previously described BTSA1 molecule, and a panel of 10 ATC cell lines, representing the entire mutation spectrum observed in patients. We generated dose-response profiles of these cell lines both in traditional 2D cell cultures and in 3D spheroid cultures, and found that EGAV1 induces prompt apoptosis in all cell lines. However, co-immunoprecipitation assays showed that EGAV1-activated BAX can still be sequestered by BCL-XL, which may reduce its efficacy. Thus, we tested the ability of the BH3 mimetic Navitoclax (ABT-263) to increase EGAV1 efficacy by inhibiting BCL-XL and BCL2. In fact, we found a dramatic decrease in the EGAV1 IC50 in the presence of a low dose of Navitoclax that has no effect as single agent. Also, we found that the efficacy of Navitoclax was equally amplified by a low dose of EGAV1. Time-course analysis of caspase 3/7 activity confirmed that these compounds induce prompt apoptosis, peaking between four and eight hours after treatment. Taken together these data suggest that there is an important therapeutic opportunity in targeting the apoptosis pathway in ATC with a BAX activator accompanied by a BH3 mimetic. Citation Format: Xhesika Shanja-Grabarz, Francesca Di Cristofano, Evripidis Gavathiotis, Antonio Di Cristofano. Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-089.