Abstract

While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

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Acknowledgements

We thank breast cancer research advocate Mrs. Jeri Francoeur for her advice and support.

Funding

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award Nos. W81XWH-15-1-0199 (BL) and W81XWH-15-1-0200 (RC). These studies were supported in part by grants from the Florida Breast Cancer Foundation (BL and RC), The Ocala Royal Dames for Cancer Research (BL), the Florida Department of Health Bankhead-Coley Program (4BF03, BL), the Collaboration of Scientists for Critical Research in Biomedicine (CSCRB, Inc., BL), and a UF-Health Cancer Center pilot project award (BL, RC, and CH). RF is grateful to the University of Florida for a Graduate School Fellowship.

Author contributions

MW, RF, ML, EY, AG, AS, BA, RC, and BL planned the studies. MW, RF, ML, BD, EY, AG, AS, and BL carried out the studies. BA, ER, CC, CH, and SN provided advice and reagents necessary for carrying out the studies. MW, RF, ML, EY, AG, AS, BA, ER, CC, SN, CH, RC, and BL edited the manuscript.

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Affiliations

  1. Department of Pharmacology, University of Florida, Gainesville, FL, 32610, USA

    • Mengxiong Wang
    • , Mary E. Law
    • , Bradley J. Davis
    • , Edgardo Rodriguez
    •  & Brian K. Law
  2. Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA

    • Renan B. Ferreira
    • , Elham Yaaghubi
    • , Amanda F. Ghilardi
    •  & Ronald K. Castellano
  3. Department of Pharmaceutics, University of Florida, Gainesville, FL, 32610, USA

    • Abhisheak Sharma
    •  & Bonnie A. Avery
  4. Institute of Molecular Medicine, College of Medicine and Center for Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

    • Chi-Wu Chiang
  5. Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, 32610, USA

    • Satya Narayan
  6. UF-Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA

    • Satya Narayan
    • , Coy D. Heldermon
    • , Ronald K. Castellano
    •  & Brian K. Law
  7. Department of Medicine, University of Florida, Gainesville, FL, 32610, USA

    • Coy D. Heldermon

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Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Ronald K. Castellano or Brian K. Law.

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DOI

https://doi.org/10.1038/s41388-019-0717-6