Bisphosphonates inactivate human EGFRs to exert antitumor actions

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Bisphosphonates are primary treatments for osteoporosis and bone metastases.
• Their role in reducing cancer progression is limited to specific patient groups, indicating a molecular mediator.
• Human epidermal growth factor receptors (HER) were investigated as a potential mediator.

Purpose of the Study:

• To identify the molecular target of bisphosphonates in cancer cells.
• To investigate the potential repurposing of bisphosphonates for cancer therapy.

Main Methods:

• Connectivity mapping was used to identify potential drug targets.
• Protein thermal shift and cell-free kinase assays were performed.
• Computational modeling was employed to understand drug-target interactions.

Main Results:

• N-containing bisphosphonates directly bind to the kinase domain of HER1/2.
• This binding reduces downstream signaling, leading to the death of lung, breast, and colon cancer cells with HER1 alterations.
• Cancer cell killing by bisphosphonates was dependent on HER isoforms, confirming HER as the mediator.

Conclusions:

• Bisphosphonates directly target and inhibit HER1/2, a key pathway in certain cancers.
• The findings support the potential repurposing of bisphosphonates for treating HER family-driven cancers.
• This study establishes a novel mechanism for bisphosphonate action in oncology.