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 BuettnerZhuan Bian, Alberta Zallone, Aneel K. Aggarwal, Shozeb Haider, Maria I. New, Li Sun, Goutham Narla, Mone Zaidi

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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 TKIresistant 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.

Original languageEnglish (US)
Pages (from-to)17995-18000
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number50
DOIs
StatePublished - Dec 16 2014
Externally publishedYes

Keywords

  • Cancer prevention
  • Cancer therapy
  • Drug repurposing

ASJC Scopus subject areas

  • General

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  • Cite this

    Stachnik, A., Yuen, T., Iqbal, J., Sgobba, M., Gupta, Y., Lu, P., Colaianni, G., Ji, Y., Zhu, L. L., Kim, S. M., Li, J., Liu, P., Izadmehr, S., Sangodkar, J., Scherer, T., Mujtaba, S., Galsky, M., Gomez, J., Epstein, S., ... Zaidi, M. (2014). Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 111(50), 17995-18000. https://doi.org/10.1073/pnas.1421422111