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

doi:10.1073/pnas.1421422111

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

Journal article

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

Agnes Stachnik, Tony Yuen, Jameel Iqbal, Miriam Sgobba, Yogesh Gupta, Ping Lu, Graziana Colaianni, Yaoting Ji, Ling-Ling Zhu, Se-Min Kim, …

Proceedings of the National Academy of Sciences - PNAS, Vol.111(50), pp.17995-18000

12/16/2014

DOI: https://doi.org/10.1073/pnas.1421422111

PMCID: PMC4273392

PMID: 25453078

Abstract

Animals

Blotting, Western

Breast Neoplasms - drug therapy

Breast Neoplasms - prevention & control

Carcinoma, Non-Small-Cell Lung - drug therapy

Carcinoma, Non-Small-Cell Lung - prevention & control

Diphosphonates - pharmacology

Diphosphonates - therapeutic use

Drug Repositioning - methods

Female

Humans

In Situ Nick-End Labeling

Mice

Mice, Inbred BALB C

Molecular Dynamics Simulation

Protein Binding

Receptor, Epidermal Growth Factor - antagonists & inhibitors

Signal Transduction - drug effects

Tetrazolium Salts

Thiazoles

Tumor Stem Cell Assay

Flow Cytometry

Immunohistochemistry

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.

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Title: Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer
Creators: Agnes Stachnik - 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
Tony Yuen - 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
Jameel Iqbal - 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
Miriam Sgobba - Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom
Yogesh Gupta - 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
Ping Lu - 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
Graziana Colaianni - 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
Yaoting Ji - 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
Ling-Ling Zhu - 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
Se-Min Kim - 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
Jianhua Li - 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
Peng Liu - 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
Sudeh Izadmehr - 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
Jaya Sangodkar - 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
Thomas Scherer - 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
Shiraz Mujtaba - 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
Matthew Galsky - 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
Jorge Gomez - 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
Solomon Epstein - 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
Christoph Buettner - 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
Zhuan Bian - Department of Research, School of Stomatology, Wuhan University, Wuhan 430079, China; and
Alberta Zallone - Department of Histology, University of Bari, Bari 70121, Italy
Aneel K Aggarwal - 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
Shozeb Haider - Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College, London WC1N 1AX, United Kingdom
Maria I New - 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
Li Sun - 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
Goutham Narla - 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
Mone Zaidi - 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
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.111(50), pp.17995-18000
Date published: 12/16/2014
Grant note: AG40132 / NIA NIH HHS Howard Hughes Medical Institute AG23176 / NIA NIH HHS DK80459 / NIDDK NIH HHS R01 AG040132 / NIA NIH HHS P30 ES023515 / NIEHS NIH HHS AR06066 / NIAMS NIH HHS R01 DK080459 / NIDDK NIH HHS AR06592 / NIAMS NIH HHS R01 AG023176 / NIA NIH HHS
Academic Unit: Medicine - Endocrinology, Metabolism and Nutrition (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665729604646