Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer
Nada H. Eisa,
Vincent M. Crowley,
Asif Elahi,
Vamsi Krishna Kommalapati,
Michael A. Serwetnyk,
Taoufik Llbiyi,
Sumin Lu,
Kashish Kainth,
Yasmeen Jilani,
Daniela Marasco,
Abdeljabar El Andaloussi,
Sukyeong Lee,
Francis T.F. Tsai,
Paulo C. Rodriguez,
David Munn,
Esteban Celis,
Hasan Korkaya,
Abdessamad Debbab,
Brian Blagg,
Ahmed Chadli
Affiliations
Nada H. Eisa
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Vincent M. Crowley
Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA
Asif Elahi
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Vamsi Krishna Kommalapati
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Michael A. Serwetnyk
Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA
Taoufik Llbiyi
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Sumin Lu
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Kashish Kainth
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Yasmeen Jilani
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Daniela Marasco
Department of Pharmacy, University of Naples “Federico II”, Via Montesano, 49, 80131 Naples, Italy
Abdeljabar El Andaloussi
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Sukyeong Lee
Departments of Biochemistry and Molecular Biology, Molecular and Cellular Biology, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
Francis T.F. Tsai
Departments of Biochemistry and Molecular Biology, Molecular and Cellular Biology, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
Paulo C. Rodriguez
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
David Munn
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Esteban Celis
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Hasan Korkaya
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA
Abdessamad Debbab
Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, Building 26.23, 40225 Düsseldorf, Germany
Brian Blagg
Department of Chemistry and Biochemistry, The University of Notre Dame, 305 McCourtney Hall, Notre Dame, IN 46556, USA
Ahmed Chadli
Georgia Cancer Center, Medical College of Georgia at Augusta University, 1410 Laney Walker Boulevard, CN-3329, Augusta, GA 30912, USA; Corresponding author
Summary: Low response rates and immune-related adverse events limit the remarkable 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) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.
