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

Abstract

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.

• Authors: 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
• 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. 17995-8000 (Dec 16 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25453078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Diphosphonates
• Tetrazolium Salts
• Thiazoles
• EGFR protein, human
• ErbB Receptors
• thiazolyl blue

Topics

• Animals
• Blotting, Western
• Breast Neoplasms (drug therapy, prevention & control)
• Carcinoma, Non-Small-Cell Lung (drug therapy, prevention & control)
• Diphosphonates (pharmacology, therapeutic use)
• Drug Repositioning (methods)
• ErbB Receptors (antagonists & inhibitors)
• Female
• Flow Cytometry
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Mice, Inbred BALB C
• Molecular Dynamics Simulation
• Protein Binding
• Signal Transduction (drug effects)
• Tetrazolium Salts
• Thiazoles
• Tumor Stem Cell Assay