Bisphosphonates May Block the Development of HER-Driven Tumors, Preventing Breast, Lung, and Colon Cancers
Two studies have found that bisphosphonates may be effective in preventing certain cancers—including lung, breast, and colon—by blocking abnormal growth signals passed through HER family receptors. The studies suggest that bisphosphonates, the most commonly prescribed medications for treating osteoporosis and skeletal metastases, can potentially be repurposed for the prevention and adjunctive therapy of HER family–driven cancers. The studies by Stachnik et al and Yuen et al are published in Proceedings of the National Academy of Sciences.
Study Methodology and Findings
Bisphosphonates have been the mainstay of therapy worldwide for osteoporosis and the prevention of bone erosion by 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 Map (CMAP), a compendium of connections between genes, diseases, and drugs, the researchers identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action.
The CMAP computational modeling, together with protein thermal shift and cell-free kinase assays, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause global reduction in downstream signaling. According to the researchers, 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,” wrote the study authors.
Using Bisphosphonates to Prevent Cancer
The researchers then conducted laboratory experiments in cancer cell cultures and mice models to investigate the potential utility of the two most commonly used FDA-approved bisphosphonates, zoledronic acid and risedronate, in the prevention and therapy of HER-driven cancers. They found that bisphosphonates inhibit the HER family receptor tyrosine kinase, including the commonly mutated forms that drive non–small cell lung cancer growth, as well as a mutation that causes resistance to tyrosine kinase inhibitors.
“This new mechanism lays the basis for the future use of bisphosphonates for the prevention and therapy of HER family–driven cancers,” wrote the researchers.
“Our study reveals a newfound mechanism that may enable the use of bisphosphonates in the future treatment and prevention of the many lung, breast, and colon cancers driven by the HER family of receptors,” said Mone Zaidi, MD, Professor of Medicine and of Structural and Chemical Biology at the Icahn School of Medicine at Mount Sinai, and a coauthor of the studies, in a statement. “Having already been approved by the FDA as effective in preventing bone loss, and having a long track record of safety, these drugs could be quickly applied to cancer if we can confirm in clinical trials that this drug class also reduces cancer growth in people. It would be much more efficient than starting drug design from scratch.”
Dr. Zaidi and Maria I. New, MD, are the corresponding authors for both Proceedings of the National Academy of Sciences articles.
Funding for these studies was provided by the National Institutes of Health, the Italian Space Agency, the National Science Foundation of China, the National Center for Advancing Translational Science through Mount Sinai School of Medicine’s Clinical and Translational Science Award, and Howard Hughes Medical Institute Physician-Scientist Early Career Award.
Dr. Zaidi, Jianhua Li, and Goutham Narla, PhD, are named inventors of a pending patent application related to the work described in these studies. There were no other conflicts of interest reported.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
