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Research Article

Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer

Agnes Stachnik, Tony Yuen, Jameel Iqbal, Miriam Sgobba, View ORCID ProfileYogesh Gupta, Ping Lu, Graziana Colaianni, Yaoting Ji, Ling-Ling Zhu, Se-Min Kim, Jianhua Li, Peng Liu, Sudeh Izadmehr, Jaya Sangodkar, Thomas Scherer, Shiraz Mujtaba, Matthew Galsky, Jorge Gomez, Solomon Epstein, Christoph Buettner, Zhuan Bian, Alberta Zallone, Aneel K. Aggarwal, Shozeb Haider, Maria I. New, Li Sun, Goutham Narla, and Mone Zaidi
  1. aDepartments 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. bDepartment of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
  3. cDepartment of Histology, University of Bari, Bari 70121, Italy;
  4. dDepartment of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and
  5. eDepartment of Medicine and Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106

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PNAS first published December 1, 2014; https://doi.org/10.1073/pnas.1421422111
Agnes Stachnik
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Tony Yuen
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Jameel Iqbal
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Miriam Sgobba
bDepartment of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
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Yogesh Gupta
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Ping Lu
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Graziana Colaianni
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
cDepartment of Histology, University of Bari, Bari 70121, Italy;
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Yaoting Ji
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
dDepartment of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and
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Ling-Ling Zhu
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
dDepartment of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and
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Se-Min Kim
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Jianhua Li
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Peng Liu
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Sudeh Izadmehr
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Jaya Sangodkar
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Thomas Scherer
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Shiraz Mujtaba
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Matthew Galsky
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Jorge Gomez
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Solomon Epstein
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Christoph Buettner
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Zhuan Bian
dDepartment of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and
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Alberta Zallone
cDepartment of Histology, University of Bari, Bari 70121, Italy;
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Aneel K. Aggarwal
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Shozeb Haider
bDepartment of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom;
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Maria I. New
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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  • For correspondence: maria.new@mssm.edu mone.zaidi@mountsinai.org
Li Sun
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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Goutham Narla
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
eDepartment of Medicine and Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH 44106
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Mone Zaidi
aDepartments of Medicine, Pediatrics, and Chemical and Structural Biology, and the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
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  • For correspondence: maria.new@mssm.edu mone.zaidi@mountsinai.org
  1. Contributed by Maria I. New, November 11, 2014 (sent for review October 2, 2014; reviewed by Wafik El-Deiry and H. Michael Shepard)

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Significance

Small molecules to target oncogenic signaling cascades in cancer have achieved success in molecularly defined patient subsets. The path to approval is often protracted and plagued with failures. Repositioning Food and Drug Administration-approved drugs with known side effects has become a major focus. Bisphosphonates are a commonly prescribed therapy for osteoporosis and skeletal metastases. The drugs have also been associated with reduced tumor burden in some patients, but the mechanism is unknown. Here we provide evidence that bisphosphonates inhibit the human EGFR (HER) receptor tyrosine kinase, including the commonly mutated forms that drive nonsmall cell lung cancer, as well as a resistance mutation. This new mechanism lays the basis for the future use of bisphosphonates for the prevention and therapy of HER family-driven cancers.

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 HER1ΔE746-A750-driven HCC827 NSCLCs and HER1wt-expressing MB231 triple negative breast cancers, but not by HERlow-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 HERlow 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.

  • drug repurposing
  • cancer therapy
  • cancer prevention

Footnotes

  • ↵1A.S. and T.Y. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: maria.new{at}mssm.edu or mone.zaidi{at}mountsinai.org.
  • ↵3L.S., G.N., and M.Z. contributed equally to this work.

  • Author contributions: T.Y., A.K.A., S.H., M.I.N., L.S., G.N., and M.Z. designed research; A.S., T.Y., J.I., M.S., Y.G., P. Lu, G.C., Y.J., L.-L.Z., S.-M.K., J.L., S.I., J.S., T.S., and L.S. performed research; A.S., T.Y., J.I., M.S., Y.G., P. Lu, G.C., S.-M.K., P. Liu, S.I., S.M., M.G., J.G., S.E., C.B., Z.B., A.Z., A.K.A., S.H., L.S., G.N., and M.Z. analyzed data; and A.S., T.Y., M.I.N., G.N., and M.Z. wrote the paper.

  • Reviewers: W.E.-D., Fox Chase Cancer Center; and H.M.S., Halozyme Therapeutics, Inc.

  • Conflict of interest statement: M.Z., J.I., and G.N. are named inventors of a pending patent application related to the work described.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1421422111/-/DCSupplemental.

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Repurposing of bisphosphonates for cancer
Agnes Stachnik, Tony Yuen, Jameel Iqbal, Miriam Sgobba, Yogesh Gupta, Ping Lu, Graziana Colaianni, Yaoting Ji, Ling-Ling Zhu, Se-Min Kim, Jianhua Li, Peng Liu, Sudeh Izadmehr, Jaya Sangodkar, Thomas Scherer, Shiraz Mujtaba, Matthew Galsky, Jorge Gomez, Solomon Epstein, Christoph Buettner, Zhuan Bian, Alberta Zallone, Aneel K. Aggarwal, Shozeb Haider, Maria I. New, Li Sun, Goutham Narla, Mone Zaidi
Proceedings of the National Academy of Sciences Dec 2014, 201421422; DOI: 10.1073/pnas.1421422111

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Repurposing of bisphosphonates for cancer
Agnes Stachnik, Tony Yuen, Jameel Iqbal, Miriam Sgobba, Yogesh Gupta, Ping Lu, Graziana Colaianni, Yaoting Ji, Ling-Ling Zhu, Se-Min Kim, Jianhua Li, Peng Liu, Sudeh Izadmehr, Jaya Sangodkar, Thomas Scherer, Shiraz Mujtaba, Matthew Galsky, Jorge Gomez, Solomon Epstein, Christoph Buettner, Zhuan Bian, Alberta Zallone, Aneel K. Aggarwal, Shozeb Haider, Maria I. New, Li Sun, Goutham Narla, Mone Zaidi
Proceedings of the National Academy of Sciences Dec 2014, 201421422; DOI: 10.1073/pnas.1421422111
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