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

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.

• Authors: 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, Brian K Law
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 17 Pg. 28971-28989 (Apr 25 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28423644 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Receptors, Estrogen
• Receptors, Progesterone
• EGFR protein, human
• ERBB2 protein, human
• ERBB3 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-3
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Breast (pathology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (metabolism)
• Female
• HEK293 Cells
• Humans
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, ErbB-2 (metabolism)
• Receptor, ErbB-3 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Signal Transduction (drug effects)
• Unfolded Protein Response (drug effects)
• Xenograft Model Antitumor Assays