title: Bisphosphonates inactivate human EGFRs to exert antitumor actions.
abstract: Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Tony
authors.initials: T
authors.lastname: Yuen
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Agnes
authors.initials: A
authors.lastname: Stachnik
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Jameel
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pharmaceutical & Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
authors.forename: Miriam
authors.initials: M
authors.lastname: Sgobba
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Histology, University of Bari, Bari 70121, Italy;
authors.forename: Graziana
authors.initials: G
authors.lastname: Colaianni
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and.
authors.forename: Yaoting
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Se-Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Jianhua
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Sudeh
authors.initials: S
authors.lastname: Izadmehr
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Jaya
authors.initials: J
authors.lastname: Sangodkar
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Jack
authors.initials: J
authors.lastname: Bailey
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Yathin
authors.initials: Y
authors.lastname: Latif
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Shiraz
authors.initials: S
authors.lastname: Mujtaba
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Solomon
authors.initials: S
authors.lastname: Epstein
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Terry F
authors.initials: TF
authors.lastname: Davies
authors.affiliation: Department of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and.
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Bian
authors.affiliation: Department of Histology, University of Bari, Bari 70121, Italy;
authors.forename: Alberta
authors.initials: A
authors.lastname: Zallone
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
authors.affiliation: Department of Pharmaceutical & Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
authors.forename: Shozeb
authors.initials: S
authors.lastname: Haider
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu mone.zaidi@mountsinai.org.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; Department of Medicine and Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.affiliation: Departments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu mone.zaidi@mountsinai.org.
authors.forename: Mone
authors.initials: M
authors.lastname: Zaidi
mesh_terms: D016880:Anisotropy; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003461:Crystallography; D004164:Diphosphonates / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D013778:Tetrazolium Salts; D013844:Thiazoles; D066246:ErbB Receptors; C022616:thiazolyl blue
keywords: Her2/neu; drug repurposing; osteoporosis; receptor tyrosine kinase; tyrosine kinase inhibitor