Abstract 3060: The cyclopeptide enniatin a inhibits the chaperone hsp90 and induces mitophagy in breast cancer cells

Abstract Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in protecting the proteome. In cancer cells, this Hsp90 function is hijacked to promote cancer cell proliferation. Except for the Pimitespib (TAS-116), approved for clinical use in Japan in 2022, no Hsp90 inhibitors have yet been approved by the FDA. One of the main side effects of the current Hsp90 inhibitors tested in the clinic is their induction of the heat shock response (HSR). Therefore, identifying new inhibitors that destabilize the oncoproteins clients of Hsp90 without inducing HSR is an attractive strategy to harness the clinical potential. We previously reported that the natural product Enniatin A (EnnA) is a novel Hsp90 inhibitor satisfying this criterion. Here, we report that EnnA potently induces mitophagy in breast cancer cells. The cytoplasmic form of Hsp90 has been shown to be more abundant in the mitochondria of tumor cells compared to mitochondria of normal tissues. We show that EnnA can enter multiple compartments of cancer cells, including the mitochondria, and inhibits Hsp90. Furthermore, we show that EnnA induces mitochondrial dynamics impairment as reflected by loss of mitochondrial membrane potential, reduced oxygen consumption rate, and loss of ATP production. We also show that targeting Hsp90 by EnnA reduced the level of cox4, a component of the electron transport chain, leading to parkin-mediated mitophagy. Our data indicate that EnnA represents a member of a new class of Hsp90 inhibitors that impair mitochondrial function in cancer cells and is a promising compound to treat breast cancer. Citation Format: Vamsi Krishna Kommalapati, Asif Elahi, Nada M. Eisa, Michael A. Serwetnyk, Abdessamad Debbab, siva panda, Daniela Marasco, Brain Blagg, Ahmed Chadli. The cyclopeptide enniatin a inhibits the chaperone hsp90 and induces mitophagy in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3060.