Related Experiment Video
Updated: Mar 4, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells
Renan B Ferreira1, Mengxiong Wang2,3, Mary E Law2,3
1Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
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.
Insights
New Disulfide bond Disrupting Agents (DDAs) show promise for treating drug-resistant breast cancers, including HER2+ and triple-negative types. These agents activate the Unfolded Protein Response (UPR), enhancing their cancer-killing ability.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Therapeutic resistance is a major cause of breast cancer mortality, particularly in HER2+ and triple-negative breast cancer (TNBC) subtypes.
- TNBCs often overexpress the Epidermal Growth Factor Receptor (EGFR), a targetable vulnerability.
- Existing therapies for HER2+ and TNBCs have limitations, necessitating novel treatment strategies.
Purpose of the Study:
- To investigate the mechanism of action for Disulfide bond Disrupting Agents (DDAs) in targeting drug-resistant breast cancers.
- To determine the role of the Unfolded Protein Response (UPR) in DDA-mediated cancer cell killing.
- To evaluate the potential of DDAs in combination therapies for overcoming treatment resistance.
Main Methods:
- Utilized breast cancer cell lines engineered to overexpress EGFR or HER2.
- Employed pharmacological probes to investigate the Unfolded Protein Response (UPR).
- Assessed DDA cytotoxicity and correlated it with specific molecular events like receptor downregulation and protein dephosphorylation.
Main Results:
- DDAs selectively kill EGFR+ and HER2+ breast cancer cells, consistent with previous findings.
- DDA treatment activates the Unfolded Protein Response (UPR) in cancer cells.
- DDA-induced cytotoxicity is mediated by HER1-3 downregulation, Akt dephosphorylation, and UPR activation, with EGFR overexpression potentiating these effects.
Conclusions:
- DDAs represent a novel class of therapeutic agents effective against resistant HER2+ and EGFR+ breast cancers.
- Activation of the UPR is a key mechanism by which DDAs exert their anti-cancer effects.
- DDAs show potential for combination therapy with existing targeted agents to overcome drug resistance in breast cancer.
More Related Videos
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
06:54Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Related Concept Videos
02:38Mitogens and the Cell Cycle
01:37The Unfolded Protein Response
01:31Regulation of the Unfolded Protein Response
01:26Protein Modifications in the RER
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...