title: Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer.
abstract: A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. Having shown that bisphosphonates, a class of drugs used widely for the therapy of osteoporosis and metastatic bone disease, reduce cancer cell viability by targeting HER1, we explored their potential utility in the prevention and therapy of HER-driven cancers. We show that bisphosphonates inhibit colony formation by HER1(ΔE746-A750)-driven HCC827 NSCLCs and HER1(wt)-expressing MB231 triple negative breast cancers, but not by HER(low)-SW620 colon cancers. In parallel, oral gavage with bisphosphonates of mice xenografted with HCC827 or MB231 cells led to a significant reduction in tumor volume in both treatment and prevention protocols. This result was not seen with mice harboring HER(low) SW620 xenografts. We next explored whether bisphosphonates can serve as adjunctive therapies to tyrosine kinase inhibitors (TKIs), namely gefitinib and erlotinib, and whether the drugs can target TKI-resistant NSCLCs. In silico docking, together with molecular dynamics and anisotropic network modeling, showed that bisphosphonates bind to TKIs within the HER1 kinase domain. As predicted from this combinatorial binding, bisphosphonates enhanced the effects of TKIs in reducing cell viability and driving tumor regression in mice. Impressively, the drugs also overcame erlotinib resistance acquired through the gatekeeper mutation T790M, thus offering an option for TKI-resistant NSCLCs. We suggest that bisphosphonates can potentially be repurposed for the prevention and adjunctive therapy of HER1-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: 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: 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: Jameel
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Department of Pharmaceutical and 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.identifier: http://orcid.org/0000-0001-6372-5007
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: Thomas
authors.initials: T
authors.lastname: Scherer
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: Matthew
authors.initials: M
authors.lastname: Galsky
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: Jorge
authors.initials: J
authors.lastname: Gomez
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: Christoph
authors.initials: C
authors.lastname: Buettner
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 and 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: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000517:prevention & control*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000517:prevention & control*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D058492:Drug Repositioning / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014410:Tumor Stem Cell Assay
chemical_list: D004164:Diphosphonates; D013778:Tetrazolium Salts; D013844:Thiazoles; C512478:EGFR protein, human; D066246:ErbB Receptors; C022616:thiazolyl blue
keywords: cancer prevention; cancer therapy; drug repurposing