Overcoming Resistance to EGFR Inhibitors in Advanced Head and Neck Cancers
Abstract
Head and neck squamous cell carcinomas (HNSCCs) affect more than a half million people annually worldwide. The goal of this proposal is to develop strategies to overcome HNSCC resistance to EGFR inhibitors (EGFRis). Based on extensive published and preliminary data, this proposal tests three hypotheses: 1) that upregulation of AURKA provides a major source of resistance to EGFRis in HPV- HNSCC. 2) that tumors most likely to upregulate AURKA will either have highly damaging LOF mutations inTP53, or upregulation of TPX2 or NEDD9, and that these tumors will have the highest level of resistance to EGFRis. 3) that targeting AURKA either with single agent kinase inhibitors, or in combination therapies that inhibit AURKA and a second protein, WEE1, that collaborates with AURKA to control mitotic progression, will be particularly effective in counteracting resistance to EGFRis. In the first year of funding, we have defined the pattern of TP53 mutations in HNSCCs. We have created HNSCC cell models resistant to EGFR-targeting inhibitors, and have been profiling response to AURKA and WEE1 inhibitors. We have accrued specimens from a clinical trial of EGFR inhibitors in HNSCC, which will support correlating therapeutic resistance with AURKA, TPX2, and NEDD9 expression. Work is ongoing
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1212849
Entities
People
- Barbara Burtness
Organizations
- Yale University