Abstract B021: CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer

Abstract

Abstract The extrinsic apoptotic pathway activates programmed cell death through the binding of extracellular death ligands, such as TNFα, to their cognate receptors. Although some death ligands are often upregulated in the tumor microenvironment, this pathway is subverted in cancer cells to instead favor growth and survival rather than the induction of apoptosis. Reflecting the strict control cancer cells exert over this pathway, functional genomics screens, such as DepMap, have identified several of the extrinsic apoptotic components as essential targets, with selective dependency in a subset of cancer cell lines. We have genetically validated that downregulation of CFLAR, a negative regulator of the extrinsic apoptosis pathway, causes apoptosis and cell growth inhibition alone, but specially in combination with TNFα signaling, across multiple cancer types, with increase prevalence in Triple-negative breast cancer. Furthermore, we have shown that in order to have maximal activity most cell lines require targeting of CFLAR short isoform splicing variant. Importantly, CFLAR downregulation in non-tumoral models presented much less activity than the observed in the sensitive cancer models supporting the selective activity of CFLAR in a subset of cancer cells. Citation Format: Victor Quereda, Shane W. O'Brien, Tony C. Della Pietra, James J. Foley, Andy Fedoriw. CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B021.