title: Novel agents that downregulate EGFR, HER2, and HER3 in parallel.
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.
authors: Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
authors: Renan Barroso
authors: RB
authors: Ferreira
authors: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors: Mary Elizabeth
authors: ME
authors: Law
authors: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors: Stephan Christopher
authors: SC
authors: Jahn
authors: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors: Bradley John
authors: BJ
authors: Davis
authors: Department of Medicine, University of Florida, Gainesville, FL, 32610, USA.
authors: Coy Don
authors: CD
authors: Heldermon
authors: Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL, 32610, USA.
authors: Mary
authors: M
authors: Reinhard
authors: Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
authors: Ronald Keith
authors: RK
authors: Castellano
authors: Department of Pharmacology & Therapeutics, University of Florida, Gainesville, FL 32610, USA.
authors: Brian Keith
authors: BK
authors: Law
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: EGFR; HER2; HER3; breast cancer; disulfide bonds