LAUSR

Low response rates and immune-related adverse events limit the impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) with these inhibitors limited their clinical efficacy as monotherapies. We discovered that Enniatin A (EnnA) binds to the interface between the middle domains of the Hsp90 dimer and destabilizes Hsp90 client oncoproteins without inducing an HSR. EnnA induces cancer cell immunogenic cell death in aggressive breast cancer models and exhibits superior anti-tumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment in syngeneic mouse models to promote CD8+ T cell-dependent anti-tumor activity mediated through a reduced level of PD-L1 and activation of CX3CR1 pathway. We propose that EnnA is a promising anti-tumor agent with a mechanism of action involving immunogenic cancer cell toxicity and mobilization of CD8+ T cells into the tumor site. Citation Format: Nada Eisa, Vincent M. Crowley, Asif Elahi, Vamsi K. Kommalapati, Hasan Korkaya, Abdessamad Debbab, Brian Blagg, Ahmed Chadli. Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2272.