Contributed by Maria I. New, November 11, 2014 (sent for review October 2, 2014; reviewed by Wafik El-Deiry and H. Michael Shepard)
Small molecules to target oncogenic signaling cascades in cancer have achieved success in molecularly defined patient subsets. The path to approval is often protracted and plagued with failures. Repositioning Food and Drug Administration-approved drugs with known side effects has become a major focus. Bisphosphonates are a commonly prescribed therapy for osteoporosis and skeletal metastases. The drugs have also been associated with reduced tumor burden in some patients, but the mechanism is unknown. Here we provide evidence that bisphosphonates inhibit the human EGFR (HER) receptor tyrosine kinase, including the commonly mutated forms that drive nonsmall cell lung cancer, as well as a resistance mutation. This new mechanism lays the basis for the future use of bisphosphonates for the prevention and therapy of HER family-driven cancers.
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 HER1ΔE746-A750-driven HCC827 NSCLCs and HER1wt-expressing MB231 triple negative breast cancers, but not by HERlow-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 HERlow 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.
↵1A.S. and T.Y. contributed equally to this work.
↵3L.S., G.N., and M.Z. contributed equally to this work.
Author contributions: T.Y., A.K.A., S.H., M.I.N., L.S., G.N., and M.Z. designed research; A.S., T.Y., J.I., M.S., Y.G., P. Lu, G.C., Y.J., L.-L.Z., S.-M.K., J.L., S.I., J.S., T.S., and L.S. performed research; A.S., T.Y., J.I., M.S., Y.G., P. Lu, G.C., S.-M.K., P. Liu, S.I., S.M., M.G., J.G., S.E., C.B., Z.B., A.Z., A.K.A., S.H., L.S., G.N., and M.Z. analyzed data; and A.S., T.Y., M.I.N., G.N., and M.Z. wrote the paper.
Reviewers: W.E.-D., Fox Chase Cancer Center; and H.M.S., Halozyme Therapeutics, Inc.
Conflict of interest statement: M.Z., J.I., and G.N. are named inventors of a pending patent application related to the work described.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1421422111/-/DCSupplemental.
