The most common osteoporosis drugs worldwide, bisphosphonates, may also prevent certain kinds of breast cancers, according to two studies led by researchers at the Icahn School of Medicine at Mount Sinai and published today in the Proceedings of the National Academy of Sciences (PNAS).
Bisphosphonates, common osteoporosis drugs, had been associated by past studies with slowed tumor growth in some patients but not others, and the mechanism behind these patterns was unknown. In the studies an international research team showed that bisphosphonates block the abnormal growth signals passed through the human EGF receptors (HER), including the forms of this protein family that make some tumors resistant to leading treatments. The connection between bisphosphonates and HER receptors was detected first in a genetic database analysis and confirmed in studies of human cancer cells and in mice.
“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 lead study author Mone Zaidi, MD, Professor of Medicine and of Structural and Chemical Biology within the Icahn School of Medicine at Mount Sinai, Director of the Mount Sinai Bone Program and a member of the Tisch Cancer Institute at Mount Sinai. “Having already been approved by the FDA as effective at 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.”
Of the two newly published PNAS papers, one describes the evidence that bisphosphonates block abnormal growth signals through HER family receptors, while the second examines the potential applications for this new mechanism: cancer prevention, combination with existing treatments, and use against treatment-resistant tumors.
Stop Abnormal Growth
The study results revolved around the human epidermal growth factor receptor (HER/EGFR) family, which consists of four types of transmembrane tyrosine kinase receptors: HER1, HER2, HER3, and HER4. HER family members occur on the surfaces of many cell types and regulate cell division and proliferation, processes closely linked to both normal tissue growth and the abnormal growth seen in cancer.
A variety of human cancers, including nonsmall cell lung (NSCLC), breast, and colon cancers, are driven by random genetic changes (somatic mutations) that make HER family receptor tyrosine kinases more active drivers of abnormal growth. About of 30 percent of nonsmall cell cancers (NSCLCs) and 90 percent of colon cancers are driven by small genetic changes in HER1, while 25 percent of breast cancers proceed from genetic changes that result in excessive amounts of HER2.
Mechanistically, HER proteins are transmembrane tyrosine kinase receptors. To drive life processes, signals must travel between cells, arrive at cell surfaces, and be passed on inside cells. When a signaling molecule like a growth factor docks into a specially shaped receptor protein on a cell’s outer surface, like a key into a lock, it changes shape of the receptor such that a biochemical message is passed on inside the cell to promote survival and growth.
In the case of a tyrosine kinase receptor, the docking of its signaling partner on the outside of the cell turns on its attached kinase inside the cell. Kinases partner with the molecule used as cellular energy currency, adenosine triphosphate (ATP), to attach a phosphate group to another molecule, which cells use like a switch to kick off chain reactions, some related to growth.
Dr. Zaidi and colleagues show that bisphosphonates themselves bind to the kinase domains of HER proteins, preventing the passing on of growth signals. For this reason, drugs that block the action of tyrosine kinases (inhibitors) like trastuzumab (Herceptin), erlotinib (Tarceva) and gefitinib (Iressa) have dramatically improved survival of cancer patients, but therapy for more than three years in a row invariably results