Oncotarget

Research Papers:

Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells

Renan B. Ferreira, Mengxiong Wang, Mary E. Law, Bradley J. Davis, Ashton N. Bartley, Paul J. Higgins, Michael S. Kilberg, Katherine E. Santostefano, Naohiro Terada, Coy D. Heldermon, Ronald K. Castellano and Brian K. Law _

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Oncotarget. 2017; 8:28971-28989. https://doi.org/10.18632/oncotarget.15952

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Abstract

Renan B. Ferreira1,*, Mengxiong Wang2,3,*, Mary E. Law2,3, Bradley J. Davis2,3, Ashton N. Bartley1, Paul J. Higgins4, Michael S. Kilberg5, Katherine E. Santostefano6, Naohiro Terada6, Coy D. Heldermon7, Ronald K. Castellano1, Brian K. Law2,3

1Department of Chemistry, University of Florida, Gainesville, FL 32611, USA

2Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA

3UF-Health Cancer Center, University of Florida, Gainesville, FL 32610, USA

4Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA

5Department of Biochemistry, University of Florida, Gainesville, FL, 32610, USA

6Department of Pathology, Immunology, and Laboratory Medicine, Center for Cellular Reprogramming, University of Florida College of Medicine, Gainesville, FL 32610, USA

7Department of Medicine, University of Florida, Gainesville, FL, 32610, USA

*These authors have contributed equally to this work

Correspondence to:

Brian K. Law, email: bklaw@ufl.edu

Ronald K. Castellano, email: castellano@chem.ufl.edu

Keywords: HER2, EGFR, UPR, Akt, breast cancer

Received: August 15, 2016     Accepted: February 12, 2017     Published: March 07, 2017

ABSTRACT

Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and “Triple-Negative” Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance.


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