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.
Pharmacology, Toxicology and Pharmaceutical Science
6
8%
Immunology and Microbiology
4
5%
Other
10
13%
Unknown
15
19%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 78. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 December 2016.
All research outputs
#698,235
of 34,601,305 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#10,958
of 119,282 outputs
Outputs of similar age
#6,934
of 423,693 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#167
of 942 outputs
Altmetric has tracked 34,601,305 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 119,282 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 40.1. This one has done particularly well, scoring higher than 90% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 423,693 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 98% of its contemporaries.
We're also able to compare this research output to 942 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 82% of its contemporaries.
