| Bisphosphonates are an FDA-approved class of drugs, used to treat diseases of the bone and cancer-related bone metastases through inhibition of osteoclast activity. Recent evidence suggests that bisphosphonates can reduce tumor burden in specific subsets of cancer, such as breast and colon cancer, independently of their action on osteoclasts. Yet, the mechanism through which bisphosphonates kill tumor cells remains unclear. An early finding through connectivity mapping revealed that the EGF Receptor (EGFR) is a molecular target of these drugs, suggesting that bisphosphonates may inhibit cancers driven by EGFR signaling. Here, I demonstrate that bisphosphonates inactivate EGFR by binding to the ATP-binding kinase domain resulting in cell cycle arrest and apoptosis. Moreover, I find that zoledronic acid exhibits synergy both in vitro and in vivo with the FDA-approved anti-EGFR-based therapy, erlotinib. These novel findings provide the molecular and biological framework for the further exploration of bisphosphonates as adjunctive therapies in the treatment of EGFR-driven cancers and for the future design of novel kinase-avid bisphosphonates. |
