Abstract 5412: Lysosome disruption rapidly and effectively induces necrosis in aggressive thyroid carcinomas

Abstract

Abstract Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are very aggressive and lethal neoplasms for which there is currently no effective therapy. By activating Kras and deleting p53 in the mouse thyroid we have generated a mouse model of PDTC progressing to ATC. These tumors are characterized by elevated levels of anti-apoptotic members of the Bcl2 family. Tumor cell lines established from this model as well as similarly aggressive human thyroid cancer cell lines undergo cell death upon treatment with Obatoclax, an inhibitor of the anti-apoptotic Bcl2 family members. Even though several studies have suggested that Obatoclax induces apoptosis or necroptosis by binding to its designated targets in a number of different cancer models, our studies show that Obatoclax induces necrosis in both human and mouse thyroid cancer cell lines. By exploiting its autofluorescence, we show that Obatoclax is found in association with lysosomes, but not with mitochondria as it would be expected given the location of its known Bcl2-family targets, and that it causes rapid lysosome disruption. Obatoclax was also able to induce a block in the later stages of autophagy, as shown by an accumulation of autophagosomes upon treatment, likely as a result of lysosome impairment. Furthermore, Bafilomycin A1, an inhibitor of lysosomal acidification, counteracts the effect of Obatoclax and allows for cell survival. These findings suggest a novel mechanism of action for Obatoclax, in which direct lysosome disruption leads to necrosis. Strikingly, human and mouse thyroid cancer cell lines are also sensitive to other lysosome-destabilizing agents. Importantly, transformed human thyroid cell lines are much more sensitive to Obatoclax than non-transformed thyroid cells, suggesting the existence of a useful therapeutic window. Even though Obatoclax has been removed from clinical trials due to low anti-tumor activity and toxic side effects, its efficacy in killing thyroid cancer cells otherwise refractory to treatment, and the alternative mechanism of action involved in this process support a new approach for targeting aggressive thyroid neoplasms. In conclusion, our data show that aggressive thyroid cancer cells are intrinsically sensitive to lysosome destabilization, and this characteristic can be exploited for the development of novel therapeutic approaches. Citation Format: Devora Champa, Antonio Di Cristofano. Lysosome disruption rapidly and effectively induces necrosis in aggressive thyroid carcinomas. [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 5412. doi:10.1158/1538-7445.AM2015-5412