Combination AURKA and WEE1 inhibition exhibits efficacy in EGFR or pan-ERBB inhibitor resistant head and neck squamous cell carcinoma

Over 600,000 cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed globally each year. Many HNSCCs overexpress the ERBB family member EGFR, and EGFR inhibitors (EGFRis) and pan-ERBB inhibitors (ERBBis) are clinically active in 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 combination of VIC-1911 with adavosertib, an inhibitor of the cell cycle checkpoint regulator WEE1, in parental versus 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 ERBB inhibitor-resistant HNSCC.