Oncotarget

Research Papers:

Novel agents that downregulate EGFR, HER2, and HER3 in parallel

Renan Barroso Ferreira, Mary Elizabeth Law, Stephan Christopher Jahn, Bradley John Davis, Coy Don Heldermon, Mary Reinhard, Ronald Keith Castellano and Brian Keith Law _

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Oncotarget. 2015; 6:10445-10459. https://doi.org/10.18632/oncotarget.3398

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Abstract

Renan Barroso Ferreira1, Mary Elizabeth Law2, Stephan Christopher Jahn2, Bradley John Davis2, Coy Don Heldermon3, Mary Reinhard4, Ronald Keith Castellano1, Brian Keith Law2

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

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

3Department of Medicine, University of Florida, Gainesville, FL, 32610, USA

4Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL, 32610, USA

Correspondence to:

Brian K. Law, e-mail: [email protected]

Ronald K. Castellano, e-mail: [email protected]

Keywords: HER2, disulfide bonds, EGFR, HER3, breast cancer

Received: January 7, 2015     Accepted: February 16, 2015     Published: March 19, 2015

ABSTRACT

EGFR, HER2, and HER3 contribute to the initiation and progression of human cancers, and are therapeutic targets for monoclonal antibodies and tyrosine kinase inhibitors. An important source of resistance to these agents arises from functional redundancy among EGFR, HER2, and HER3. EGFR family members contain conserved extracellular structures that are stabilized by disulfide bonds. Compounds that disrupt extracellular disulfide bonds could inactivate EGFR, HER2, and HER3 in unison. Here we describe the identification of compounds that kill breast cancer cells that overexpress EGFR or HER2. Cell death parallels downregulation of EGFR, HER2, and HER3. These compounds disrupt disulfide bonds and are termed Disulfide Bond Disrupting Agents (DDAs). DDA RBF3 exhibits anticancer efficacy in vivo at 40 mg/kg without evidence of toxicity. DDAs may complement existing EGFR-, HER2-, and HER3-targeted agents that function through alternate mechanisms of action, and combination regimens with these existing drugs may overcome therapeutic resistance.


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