Bisphosphonates inactivate human EGFRs to exert antitumor actions

Tony Yuen, Agnes Stachnik, 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, Jack Bailey, Yathin Latif, Shiraz Mujtaba, Solomon Epstein, Terry F. Davies, Zhuan BianAlberta Zallone, Aneel K. Aggarwal, Shozeb Haider, Maria I. New, Li Sun, Goutham Narla, Mone Zaidi

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)17989-17994
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number50
StatePublished - Dec 16 2014
Externally publishedYes


  • Drug repurposing
  • Her2/neu
  • Osteoporosis
  • Receptor tyrosine kinase
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • General


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