Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 50, Pages 17989-17994Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1421410111
Keywords
tyrosine kinase inhibitor; drug repurposing; Her2/neu; receptor tyrosine kinase; osteoporosis
Categories
Funding
- National Institutes of Health [DK80459, AG40132, AG23176, AR06592, AR06066]
- Italian Space Agency
- National Science Foundation of China, Ministry of China
- National Center for Advancing Translational Sciences, National Institutes of Health, through Icahn School of Medicine at Mount Sinai's Clinical and Translational Science Award
- Howard Hughes Medical Institute Physician-Scientist Early Career Award [KL2TR000069]
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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.
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