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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324492 | GEO | 2026/07/28

REPOSITORIES: GEO

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Project description:Estrogen receptor-positive breast cancer (ER+BC) represent about 70% of all breast cancer cases. Approximately 30-50% of ER+BCs eventually develop resistance to primary endocrine therapy and progress to metastatic disease. The addition of cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) to endocrine therapy has improved disease control in advanced and metastatic ER+BC. However, progression on CDK4/6i is common and further research is required to fully understand and overcome the mechanisms of CDK4/6i resistance in ER+BC. We performed single-cell RNA sequencing (scRNA-seq) of temporal tumor samples from the FELINE clinical trial (NCT02712723) to uncover emergent resistance phenotypes in ER+BC patients receiving a combination of ribociclib with letrozole or letrozole alone in a neoadjuvant setting. In the majority of patient tumors, resistant cancer cells activated ErbB growth factor signaling during treatment, with an upregulation in ERBB2 and ERBB4 in post-treatment cells, as well as increased activity of transcription factors downstream of ErbB signaling. This indicates that endocrine therapy plus CDK4/6i activated compensatory ErbB growth factor signaling in resistant cells, supporting an established estrogen-independent state of proliferation. To further understand this shift in cell state, we used afatinib, an ErbB family blocker, in combination with ribociclib to target this resistance mechanism. We developed multiple in vitro three-dimensional ER+BC cell culture models that are sensitive or resistant to ribociclib. Samples were collected regularly during monotherapy or combination of ribociclib and afatinib treatment and bulk RNA-sequencing measured the dynamical changes in the cell state over short and long timescales. Generalized additive models quantitatively evaluated cancer cell plasticity and synergy of combination therapy using the RNA-seq data. Our models revealed how activity of signaling pathways drive transcriptional changes in cell cycle regulators that promote or inhibit cell cycle progression. We found that ribociclib plus afatinib synergize to promote early and sustained cell cycle arrest, and later apoptosis, in both sensitive and resistant cells. Combination therapy simultaneously restored G1/S phase regulation by inhibiting the cyclin E/CDK2 complex and enforced G2/M phase control by inhibiting the cyclin B/CDK1 complex, thereby blocking entry into mitosis. This dual inhibition strategy not only controlled cancer proliferation, but also induced caspase-dependent apoptosis. Overall, our study revealed a key CDK4/6i resistance mechanism, and demonstrated that a combination of ribociclib plus afatinib overcomes intrinsic mechanisms of resistance in ER+BC.

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

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