Bisphosphonates inactivate human EGFRs to exert antitumor actions.

Abstract

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.

• Authors: 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 Bian, Alberta Zallone, Aneel K Aggarwal, Shozeb Haider, Maria I New, Li Sun, Goutham Narla, Mone Zaidi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 50 Pg. 17989-94 (Dec 16 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25453081 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Diphosphonates
• Tetrazolium Salts
• Thiazoles
• ErbB Receptors
• thiazolyl blue

Topics

• Anisotropy
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Crystallography
• Diphosphonates (metabolism, pharmacology)
• ErbB Receptors (antagonists & inhibitors, chemistry, metabolism)
• Fluorescence
• Humans
• Models, Molecular
• Molecular Dynamics Simulation
• Protein Binding
• Protein Conformation
• Tetrazolium Salts
• Thiazoles