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Combination AURKA and WEE1 Inhibition Exhibits Efficacy in EGFR or Pan-ERBB Inhibitor-Resistant Head and Neck Squamous Cell Carcinoma
Journal article   Peer reviewed

Combination AURKA and WEE1 Inhibition Exhibits Efficacy in EGFR or Pan-ERBB Inhibitor-Resistant Head and Neck Squamous Cell Carcinoma

Flaviane N Silva, Jong Woo Lee, Theodore T Nguyen, Fiona M Goeckel, Tetyana Bagnyukova, Hossein Borghaei, Erica A Golemis and Barbara A Burtness
Cancer research communications, v 6(8), p1916
30 Jul 2026
DOI: https://doi.org/10.1158/2767-9764.CRC-26-0368
PMID: 42531323
url
https://doi.org/10.1158/2767-9764.CRC-26-0368View
Published, Version of Record (VoR) Open

Abstract

Animals Aurora Kinase A - antagonists & inhibitors Aurora Kinase A - metabolism Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - metabolism Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Epithelial-Mesenchymal Transition - drug effects ErbB Receptors - antagonists & inhibitors Erlotinib Hydrochloride - pharmacology Female Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - pathology Humans Mice Nuclear Proteins - antagonists & inhibitors Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - metabolism Pyrazoles - pharmacology Pyrimidines - pharmacology Pyrimidinones Squamous Cell Carcinoma of Head and Neck - drug therapy Squamous Cell Carcinoma of Head and Neck - genetics Squamous Cell Carcinoma of Head and Neck - metabolism Squamous Cell Carcinoma of Head and Neck - pathology Xenograft Model Antitumor Assays
More than 600,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally each year. Many HNSCCs overexpress the ERBB family member epidermal growth factor receptor (EGFR), and EGFR inhibitors (EGFRi) and pan-ERBB inhibitors (ERBBi) are clinically active in the treatment of locally advanced, metastatic, or recurrent HNSCC. However, resistance to these inhibitors typically develops, often associated with epithelial-mesenchymal transition (EMT). Aurora kinase A (AURKA), a mitotic regulator with expanded signaling functions in tumors, has been reported to reverse EGFR resistance in EGFR-mutated lung cancer. To identify strategies to overcome resistance in HNSCC, we developed HNSCC cell models that were treatment-naïve parental or selected for resistance to the EGFRi erlotinib or the ERBBi afatinib. The resistant HNSCC models had typically undergone partial EMT, consistent with clinical resistance, associated with upregulation of the AURKA partner protein NEDD9. Synergy of the AURKA inhibitor VIC-1911 with erlotinib or afatinib in parental models was reduced in resistant models in short-term growth assays. In longer-term clonogenic assays and in vivo, cells selected for EGFRi/ERBBi resistance showed heightened sensitivity to VIC-1911, contributing to reduced synergy. Based on increased AURKA dependence, we compared the combination of VIC-1911 with adavosertib, an inhibitor of the cell-cycle checkpoint regulator WEE1, in parental and resistant models. These showed a combination effect both in vitro and in vivo that was retained in ERBBi-resistant xenografts, suggesting the potential value of combined AURKA and WEE1 inhibitor use in patients with ERBBi-resistant HNSCC. Treatment resistance is a major source of mortality for HNSCC. This study investigates strategies to overcome resistance to inhibitors of the ERBB family, which are commonly used for the treatment of advanced HNSCC. The results suggest the value of the use of combined AURKA and WEE inhibition in the resistance setting.

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