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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17989-94. doi: 10.1073/pnas.1421410111. Epub 2014 Dec 1.

Bisphosphonates inactivate human EGFRs to exert antitumor actions.

Author information

1
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;
2
Department of Pharmaceutical & Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
3
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;
4
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.
5
Department of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and.
6
Department of Histology, University of Bari, Bari 70121, Italy;
7
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.
8
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.

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.

KEYWORDS:

Her2/neu; drug repurposing; osteoporosis; receptor tyrosine kinase; tyrosine kinase inhibitor

Comment in

PMID:
25453081
PMCID:
PMC4273397
DOI:
10.1073/pnas.1421410111
[Indexed for MEDLINE]
Free PMC Article

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