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1.
Oncotarget ; 6(12): 10445-59, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-25865227

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.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , ErbB Receptors/metabolism , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Female , Humans , Mice , Models, Molecular , Molecular Targeted Therapy , Phosphorylation , Random Allocation , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
2.
Front Biosci (Schol Ed) ; 4(2): 749-66, 2012 01 01.
Article in English | MEDLINE | ID: mdl-22202088

ABSTRACT

The TGF-beta signaling pathway controls multiple functions of cancer cells and the surrounding stromal tissue. Some TGF-beta actions suppress cancer formation, while others contribute to tumor progression. Evidence supporting a tumor suppressive role for the TGF-beta/Smad signaling axis is presented here. These data are compiled from cell culture studies, animal models, analyses of human tumors, and investigations of polymorphisms of TGF-beta pathway components and their associated cancer risk. Therapeutic strategies for cancer treatment involving either restoring or potentiating TGF-beta tumor suppressive activities, or blocking TGF-beta tumor promoting functions are considered.


Subject(s)
Neoplasms/metabolism , Transforming Growth Factor beta/metabolism , Animals , Cell Growth Processes/drug effects , Cell Growth Processes/physiology , Humans , Neoplasms/drug therapy , Neoplasms/pathology , Receptors, Transforming Growth Factor beta/metabolism , Signal Transduction , Transforming Growth Factor beta/antagonists & inhibitors
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