Abstract C094: Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis

Abstract

Abstract Flotillin-1 contributes to invasion and metastasis in triple negative breast cancer (TNBC). Palmitoylation, the process of conjugating palmitoyl-CoA to proteins, plays an essential role in protein stability and trafficking. Flotillin-1 is modified through palmitoylation, however, the role of its palmitoylation in the context of metastasis has not been explored. Using palmitoylation defective flotillin-1 constructs and loss of function experiments, we have demonstrated that flotillin-1 palmitoylation contributes to its protein stability and metastatic capabilities in vivo. To assess the ability to target flotillin-1 palmitoylation therapeutically, we designed a competitive peptide, which displayed efficacy in blocking flotillin-1 palmitoylation in vitro without altering palmitoylation of other zDHHC5 substrates, highlighting its specificity. Additionally, multiple TNBC tumor models displayed attenuated lung metastasis when expressing a doxycycline inducible flotillin-1 palmitoylation inhibiting peptide construct. The current study has demonstrated the palmitoylation of flotillin-1, a known metastasis inducing protein, to be essential for its protein stability. The demonstrated methods in blocking its palmitoylation through the delivery of a competitive peptide provide proof-of-concept data for further development as a potential targeted therapeutic in TNBC. Citation Format: Bryan McClellan, Linda de Graffenried. Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C094.